Details of the Researcher

PHOTO

Naoki Suzuki
Section
Graduate School of Medicine
Job title
Associate Professor
Degree

  • 博士（医学）（東北大学）

e-Rad No.
70451599
Profile

Since becoming a physician in 2001, I have been involved in clinical practice as a neurologist. Additionally, I have consistently conducted research on the pathophysiology and treatment of neuromuscular diseases such as ALS, inclusion body myositis, dysferlinopathies, and GNE myopathy. Utilizing various methods including iPSCs, genetic analysis, omics analysis, animal models, and neuromuscular pathology, I aim to uncover the molecular mechanisms underlying the resilience of motor neuron axons over a century of function and the repair of cell membranes and removal of unnecessary proteins in skeletal muscles constantly exposed to mechanical stress. With a fervent passion for science, my goal is to translate research findings into clinical applications. From 2024, I have also been studying rehabilitation medicine to further enhance my knowledge and contribute to overcoming rare diseases and disabilities, for the benefit of both individuals and society.

[Empowering Lives, Embracing Challenges: Overcoming Rare Diseases and Disabilities]

Research History 9

  • 2025/04 - Present
    Tohoku University　Department of Rehabilitation Medicine, Tohoku University Graduate School of Medicine　Associate Professor

  • 2024/04 - 2025/04
    Tohoku University Graduate School of Medicine　Department of Rehabilitation Medicine　Senior Lecturer

  • 2020/10 - 2024/03
    Tohoku University　University Hospital　Assistant Professor

  • 2019/10 - 2020/09
    Shodo-kai Southern Tohoku General Hospital　medical director

  • 2015 - 2019/09
    Tohoku University

  • 2011/11 - 2014/09
    Harvard University, Department of Stem Cell and Regenerative Biology

  • 2007/04 - 2011/10
    Department of Neurology, Tohoku University

  • 2004/04 - 2007/03
    NCNP

  • 2003/04 - 2007/03
    Tohoku University Graduate School of Medicine

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Education 3

  • Tohoku University　Graduate School of Medicine

    2003/04 - 2007/03

  • Tohoku University　Faculty of Medicine　School of Medicine

    1995/04 - 2001/03

  • Sugamo Gakuen

    1992/04 - 1995/03

Professional Memberships 14

  • 日本筋学会

  • 日本神経科学会

  • 日本神経学会

  • The Japan Geriatrics Society

    2023/06 -

  • 日本リハビリテーション医学会

  • 日本脳卒中学会

  • JAPAN SOCIETY FOR DEMENTIA RESEARCH

  • World Muscle Society

  • ISSCR

  • Society of Neuroscience

  • THE JAPANESE SOCIETY OF INFLAMMATION AND REGENERATION

  • THE JAPANESE SOCIETY FOR REGENERATIVE MEDICINE

  • THE JAPAN SOCIETY OF HUMAN GENETICS

  • 日本内科学会

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Research Interests 22

  • Aging

  • Sarcopenia

  • neuromuscular junction (NMJ)

  • rehabilitation

  • GNE myopathy

  • mechanobiology

  • axonal resilience

  • membrane repair

  • TDP-43

  • iPS cell

  • C9ORF72

  • muscle atrophy

  • Amyotrophic Lateral Sclerosis (ALS)

  • FUS/TLS (fused in sarcoma/translocated in liposarcoma)

  • Genetic analysis

  • SOD1

  • nitric oxide

  • proteasome / autophagy

  • sporadic inclusion body myositis (sIBM)

  • regenerative medicine

  • Muscular dystrophy

  • dysferlin

Research Areas 7

  • Life sciences / Biomedical engineering /

  • Life sciences / Rehabilitation science /

  • Life sciences / Cell biology /

  • Life sciences / Molecular biology /

  • Life sciences / Medical biochemistry /

  • Life sciences / Neuroscience - general /

  • Life sciences / Neurology /

Awards 16

  1. 研究開発助成

    2022　公益財団法人 ライフサイエンス振興財団

  2. 2022年度 開発研究助成

    2022　公益財団法人 中谷医工計測技術振興財団

  3. 公益財団法人 持田記念医学薬学振興財団 研究助成金

    2021

  4. 第4回 せりか基金賞

    2020

  5. 医学系研究助成（精神・神経・脳領域）

    2020　武田科学振興財団

  6. The Kanae Foundation for the Promotion of Medical Science

    2017

  7. Japan Intractable Diseases Research Foundation

    2016

  8. 公益信託「生命の彩」ALS研究助成基金

    2016

  9. 平成22年度治験実施優良者

    2011　東北大学病院

  10. 持田記念医学薬学振興財団 留学補助金

    2011

  11. 武田科学振興財団 医学系研究奨励

    2011

  12. 22th Lilly Scientific Fellowship Program （Selected by Japanese Society of Neurology）

    2011

  13. 中冨健康科学財団 研究助成金

    2010

  14. The Best Teacher Awards

    2009

  15. The Best Teacher Awards

    2007

  16. The WMS-Elsevier Membership Award, World Muscle Society

    2006

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Papers 212

  1. Harnessing synaptic vesicle release and recycling with antibody shuttle for targeted delivery of therapeutics to neurons. International-journal

    Karen Kar Lye Yee, Junichi Kumamoto, Daijiro Inomata, Naoki Suzuki, Ryuhei Harada, Norihiro Yumoto

    Molecular therapy. Methods & clinical development　33　(2)　101476-101476　2025/06/12

    DOI： 10.1016/j.omtm.2025.101476 　

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    The effective delivery of therapeutic molecules to neurons are mainly limited by the presence of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), leading to suboptimal therapeutic outcomes in neurodegenerative diseases treatment. This study introduces a neuron-selective drug delivery system that utilizes the synaptic vesicle release and recycling mechanism (SVRM) to overcome these barriers. This delivery system consists of an antibody shuttle that targets SV transmembrane proteins, which enables selective molecule delivery to neurons. We demonstrated that intravenously administered antibodies raised against the luminal domain of synaptotagmin-2 (SYT2) selectively localize to neuromuscular junctions. They were taken up and retrogradely transported to CHAT-positive motor neurons in both the spinal cord and brainstem. Anti-SYT2 antibody delivery of anti-microtubule agent and MALAT1 gapmer antisense oligonucleotides (ASOs) induces axonal degeneration and MALAT1 RNA downregulation in vitro, respectively. Additionally, intravenous administration of anti-SYT2 conjugated with MALAT1 gapmer ASOs in mice resulted in the reduction of Malat1 RNA in targeted cells. This approach circumvents the BSCB, enabling the neuron-selective delivery of therapeutic agents to increase neuronal drug concentrations while minimizing off-target effects in non-targeted cells. Thus, harnessing the SVRM offers a promising strategy to enhance the therapeutic index for neurodegenerative diseases treatment.

  2. Jacifusen for FUS-ALS: molecular effects and clinical outcomes in a case series. International-journal

    Naoki Suzuki, Ayumi Nishiyama, Satoru Ebihara, Masashi Aoki

    Lancet (London, England)　405　(10494)　2028-2030　2025/06/07

    DOI： 10.1016/S0140-6736(25)01038-4 　

  3. Ultra-Orphan drug development for GNE Myopathy: A synthetic literature review and meta-analysis International-journal

    Naoki Suzuki, Madoka Mori-Yoshimura, Ichizo Nishino, Masashi Aoki

    Journal of Neuromuscular Diseases　12　(2)　183-194　2025/03

    DOI： 10.1177/22143602241296226 　

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    GNE myopathy is an autosomal recessive hereditary muscle disorder that has the following clinical characteristics: develops in early adulthood, gradually progresses from the distal muscles, and is relatively sparing of quadriceps until the advanced stages of the disease. With further progression, patients become non-ambulatory and need a wheelchair. There is growing concern about extra-muscular presentations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Pathologically, rimmed vacuoles and tubulofilamentous inclusions are observed in affected muscles. The cause of the disease is thought to be a sialic acid deficiency due to mutations of the GNE gene required for in vivo sialic acid biosynthesis. Sialic acid supplementation to a presymptomatic GNE myopathy mouse model was effective in preventing the development of the disease. Several clinical studies have been conducted to evaluate the safety and efficacy of sialic acid supplementation in humans. Based on the favorable results of these studies, an extended-release aceneuramic acid formulation was approved for treatment of GNE myopathy in Japan in March 2024. It is anticipated that it will be a significant step in the development of an effective treatment for GNE myopathy and other ultra-orphan diseases.

  4. Swift induction of human spinal lower motor neurons and robust ALS cell screening via single-cell imaging. International-journal

    Selena Setsu, Satoru Morimoto, Shiho Nakamura, Fumiko Ozawa, Kagistia Hana Utami, Ayumi Nishiyama, Naoki Suzuki, Masashi Aoki, Yukio Takeshita, Yukihide Tomari, Hideyuki Okano

    Stem cell reports　20　(1)　102377-102377　2025/01/14

    DOI： 10.1016/j.stemcr.2024.11.007 　

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    This study introduces a novel method for rapidly and efficiently inducing human spinal lower motor neurons (LMNs) from induced pluripotent stem cells (iPSCs) to eventually elucidate the pathomechanisms of amyotrophic lateral sclerosis (ALS) and facilitate drug screening. Previous methods were limited by low induction efficiency, poor LMN purity, or labor-intensive induction and evaluation processes. Our protocol overcomes these challenges, achieving around 80% induction efficiency within just two weeks by combining a small molecule-based approach with transcription factor transduction. Moreover, to exclude non-LMN cells from the analysis, we utilized time-lapse microscopy and machine learning to analyze the morphology and viability of iPSC-derived LMNs on a single-cell basis, establishing an effective pathophysiological evaluation system. This rapid, efficient, and streamlined protocol, along with our single-cell-based evaluation method, enables large-scale analysis and drug screening using iPSC-derived motor neurons.

  5. Updated Genetic Analysis of Japanese Familial ALS Patients Carrying SOD1 Variants Revealed Phenotypic Differences for Common Variants

    Ayumi Nishiyama, Tetsuya Niihori, Naoki Suzuki, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Ryo Funayama, Keiko Nakayama, Hitoshi Warita, Yoko Aoki, Masashi Aoki

    Neurology Genetics　2024/12

    DOI： 10.1212/NXG.0000000000200196 　

  6. ALS-associated RNA binding proteins converge onUNC13Atranscription through regulation of REST

    Yasuaki Watanabe, Naoki Suzuki, Tadashi Nakagawa, Masaki Hosogane, Tetsuya Akiyama, Hitoshi Warita, Masashi Aoki, Keiko Nakayama

    2024/10/23

    DOI： 10.1101/2024.10.22.619761 　

  7. Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis

    Kensuke Okada, Daisuke Ito, Satoru Morimoto, Chris Kato, Yuki Oguma, Hitoshi Warita, Naoki Suzuki, Masashi Aoki, Junko Kuramoto, Reona Kobayashi, Munehisa Shinozaki, Masahito Ikawa, Jin Nakahara, Shinichi Takahashi, Yoshinori Nishimoto, Shinsuke Shibata, Hideyuki Okano

    Brain　2024/09/23

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/brain/awae224 　

    ISSN： 0006-8950

    eISSN： 1460-2156

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    Abstract Advanced pathological and genetic approaches have revealed that mutations in fused in sarcoma/translated in liposarcoma (FUS/TLS), which is pivotal for DNA repair, alternative splicing, translation and RNA transport, cause familial amyotrophic lateral sclerosis (ALS). The generation of suitable animal models for ALS is essential for understanding its pathogenesis and developing therapies. Therefore, we used CRISPR-Cas9 to generate FUS-ALS mutation in the non-classical nuclear localization signal (NLS), H517D (mouse position: H509D) and genome-edited mice. Fus WT/H509D mice showed progressive motor impairment (accelerating rotarod and DigiGait system) with age, which was associated with the loss of motor neurons and disruption of the nuclear lamina and nucleoporins and DNA damage in spinal cord motor neurons. We confirmed the validity of our model by showing that nuclear lamina and nucleoporin disruption were observed in lower motor neurons differentiated from patient-derived human induced pluripotent stem cells (hiPSC-LMNs) with FUS-H517D and in the post-mortem spinal cord of patients with ALS. RNA sequence analysis revealed that most nuclear lamina and nucleoporin-linking genes were significantly decreased in FUS-H517D hiPSC-LMNs. This evidence suggests that disruption of the nuclear lamina and nucleoporins is crucial for ALS pathomechanisms. Combined with patient-derived hiPSC-LMNs and autopsy samples, this mouse model might provide a more reliable understanding of ALS pathogenesis and might aid in the development of therapeutic strategies.

  8. Safety and efficacy of aceneuramic acid in GNE myopathy: open-label extension study. International-journal

    Naoki Suzuki, Madoka Mori-Yoshimura, Masahisa Katsuno, Masanori P Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Journal of neurology, neurosurgery, and psychiatry　95　(11)　1093-1094　2024/06/05

    DOI： 10.1136/jnnp-2024-333853 　

  9. Nationwide survey of patients with multisystem proteinopathy in Japan International-journal

    Satoshi Yamashita, Yuji Takahashi, Jun Hashimoto, Ayuka Murakami, Ryoichi Nakamura, Masahisa Katsuno, Rumiko Izumi, Naoki Suzuki, Hitoshi Warita, Masashi Aoki

    Annals of Clinical and Translational Neurology　11　(4)　938-945　2024/01/29

    DOI： 10.1002/acn3.52011 　

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    OBJECTIVE: Multisystem proteinopathy (MSP) is an inherited disorder in which protein aggregates with TAR DNA-binding protein of 43 kDa form in multiple organs. Mutations in VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, and ANXA11 are causative for MSP. This study aimed to conduct a nationwide epidemiological survey based on the diagnostic criteria established by the Japan MSP study group. METHODS: We conducted a nationwide epidemiological survey by administering primary and secondary questionnaires among 6235 specialists of the Japanese Society of Neurology. RESULTS: In the primary survey, 47 patients with MSP were identified. In the secondary survey of 27 patients, inclusion body myopathy was the most common initial symptom (74.1%), followed by motor neuron disease (11.1%), frontotemporal dementia (FTD, 7.4%), and Paget's disease of bone (PDB, 7.4%), with no cases of parkinsonism. Inclusion body myopathy occurred most frequently during the entire course of the disease (81.5%), followed by motor neuron disease (25.9%), PDB (18.5%), FTD (14.8%), and parkinsonism (3.7%). Laboratory findings showed a high frequency of elevated serum creatine kinase levels and abnormalities on needle electromyography, muscle histology, brain magnetic resonance imaging, and perfusion single-photon emission computed tomography. INTERPRETATION: The low frequency of FTD and PDB may suggest that FTD and PDB may be widely underdiagnosed and undertreated in clinical practice.

  10. Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy. International-journal

    Rumiko Izumi, Kensuke Ikeda, Tetsuya Niihori, Naoki Suzuki, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki

    Annals of clinical and translational neurology　11　(3)　577-592　2023/12/29

    DOI： 10.1002/acn3.51977 　

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    OBJECTIVE: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3. METHODS: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues. RESULTS: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs. INTERPRETATION: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.

  11. Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients. International-journal

    Ryoichi Nakamura, Genki Tohnai, Masahiro Nakatochi, Naoki Atsuta, Hirohisa Watanabe, Daisuke Ito, Masahisa Katsuno, Akihiro Hirakawa, Yuishin Izumi, Mitsuya Morita, Takehisa Hirayama, Osamu Kano, Kazuaki Kanai, Nobutaka Hattori, Akira Taniguchi, Naoki Suzuki, Masashi Aoki, Ikuko Iwata, Ichiro Yabe, Kazumoto Shibuya, Satoshi Kuwabara, Masaya Oda, Rina Hashimoto, Ikuko Aiba, Tomohiko Ishihara, Osamu Onodera, Toru Yamashita, Koji Abe, Kouichi Mizoguchi, Toshio Shimizu, Yoshio Ikeda, Takanori Yokota, Kazuko Hasegawa, Fumiaki Tanaka, Kenji Nakashima, Ryuji Kaji, Jun-Ichi Niwa, Manabu Doyu, Chikashi Terao, Shiro Ikegawa, Koki Fujimori, Shiho Nakamura, Fumiko Ozawa, Satoru Morimoto, Kazunari Onodera, Takuji Ito, Yohei Okada, Hideyuki Okano, Gen Sobue

    Journal of neurology, neurosurgery, and psychiatry　94　(10)　816-824　2023/10

    DOI： 10.1136/jnnp-2022-330851 　

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    BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

  12. Efficacy confirmation study of aceneuramic acid administration for GNE myopathy in Japan International-journal

    Madoka Mori-Yoshimura, Naoki Suzuki, Masahisa Katsuno, Masanori P. Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Orphanet Journal of Rare Diseases　18　(1)　241-241　2023/08/11

    Publisher: Springer Science and Business Media {LLC}

    DOI： 10.1186/s13023-023-02850-y 　

    ISSN： 1750-1172

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    <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>A rare muscle disease, GNE myopathy is caused by mutations in the <jats:italic>GNE</jats:italic> gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (− 0.115 kg) was numerically smaller as compared with placebo (− 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (− 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy.</jats:p> <jats:p><jats:italic>Trial registration number</jats:italic>: ClinicalTrials.gov (NCT04671472).</jats:p> </jats:sec>

  13. LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits. International-journal

    Dan Li, Yoshikazu Johmura, Satoru Morimoto, Miyuki Doi, Keiko Nakanishi, Manabu Ozawa, Yuji Tsunekawa, Akane Inoue-Yamauchi, Hiroya Naruse, Takashi Matsukawa, Yukio Takeshita, Naoki Suzuki, Masashi Aoki, Ayumi Nishiyama, Xin Zeng, Chieko Konishi, Narumi Suzuki, Atsuya Nishiyama, Alexander Stephen Harris, Mariko Morita, Kiyoshi Yamaguchi, Yoichi Furukawa, Kenta Nakai, Shoji Tsuji, Satoshi Yamazaki, Yuji Yamanashi, Shoichi Shimada, Takashi Okada, Hideyuki Okano, Tatsushi Toda, Makoto Nakanishi

    Nature aging　3　(8)　1001-1019　2023/07/20

    DOI： 10.1038/s43587-023-00464-4 　

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    Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.

  14. Pathogenic role of anti-cN1A autoantibodies in sporadic inclusion body myositis International-journal

    Satoshi Yamashita, Nozomu Tawara, Ziwei Zhang, Shunya Nakane, Kazuma Sugie, Naoki Suzuki, Ichizo Nishino, Masashi Aoki

    Journal of Neurology, Neurosurgery & Psychiatry　94　(12)　1018-1024　2023/07/14

    DOI： 10.1136/jnnp-2023-331474 　

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    BACKGROUND: Sporadic inclusion body myositis (sIBM) is an intractable muscle disease that frequently affects elderly people. Autoantibodies recognising cytosolic 5'-nucleotidase 1A (cN1A) were found in the sera of patients with sIBM. However, the pathogenic role of the autoantibodies remained unknown. This study investigated the pathogenic properties of the autoantibodies using active cN1A peptides immunisation. METHODS: Wild-type C57BL6 mice were injected with three different mouse cN1A peptides corresponding to the previously reported epitope sequences of human cN1A. After confirming the production of autoantibodies to the corresponding cN1A peptides in each group, changes in body weight, exercise capacity by treadmill test and histological changes in mice injected with cN1A peptides or controls were investigated. RESULTS: Autoantibodies against cN1A were detected in serum samples from mice injected with cN1A peptide. Some groups of mice injected with cN1A peptide showed significant weight loss and decreased motor activity. The number of myofibres with internal nuclei increased in all the peptide-injected groups, with surrounding or invading CD8-positive T cells into myofibres, abnormal protein aggregates and overexpression of p62 and LC3. CONCLUSIONS: Active cN1A peptide immunisation partially reproduced the clinical and histological aspects of sIBM in wild-type mice. The murine model demonstrates the pathogenic properties of anti-cN1A autoantibodies to cause sIBM-like histological changes.

  15. Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery. International-journal

    Satoru Morimoto, Shinichi Takahashi, Daisuke Ito, Yugaku Daté, Kensuke Okada, Chris Kato, Shiho Nakamura, Fumiko Ozawa, Chai Muh Chyi, Ayumi Nishiyama, Naoki Suzuki, Koki Fujimori, Tosho Kondo, Masaki Takao, Miwa Hirai, Yasuaki Kabe, Makoto Suematsu, Masahiro Jinzaki, Masashi Aoki, Yuto Fujiki, Yasunori Sato, Norihiro Suzuki, Jin Nakahara, Hideyuki Okano

    Cell stem cell　30　(6)　766-780　2023/06/01

    DOI： 10.1016/j.stem.2023.04.017 　

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    iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.

  16. Phase II/III Study of Aceneuramic Acid Administration for GNE Myopathy in Japan. International-journal

    Naoki Suzuki, Madoka Mori-Yoshimura, Masahisa Katsuno, Masanori P Takahashi, Satoshi Yamashita, Yasushi Oya, Atsushi Hashizume, Shinichiro Yamada, Masayuki Nakamori, Rumiko Izumi, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Journal of neuromuscular diseases　10　(4)　555-566　2023/04/25

    DOI： 10.3233/JND-230029 　

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    BACKGROUND: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far. OBJECTIVE: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy. METHODS: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point. RESULTS: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was -0.1 kg (-2.1 to 2.0) in the SA-ER group and -5.1 kg (-10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (-0.3 to 9.9; P = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed. CONCLUSIONS: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan.

  17. Patients with lower limb-onset ALS who have a longer duration from onset to diagnosis have a better prognosis

    Tomomi Shijo, Naoki Suzuki, Hitoshi Warita, Yuko Kawauchi, Shio Mitsuzawa, Kensuke Ikeda, Rumiko Izumi, Risako Ono, Akiyuki Ohno, Masaya Toyoshima, Ryuhei Harada, Hiroshi Kuroda, Masaaki Kato, Masashi Aoki

    NEUROLOGY AND CLINICAL NEUROSCIENCE　10　(5)　239-244　2022/09

    DOI： 10.1111/ncn3.12652 　

    ISSN： 2049-4173

  18. RSPO3 is a novel contraction-inducible factor identified in an "in vitro exercise model" using primary human myotubes. International-journal

    Tadahisa Takahashi, Yuqing Li, Weijian Chen, Mazvita R Nyasha, Kazumi Ogawa, Kazuaki Suzuki, Masashi Koide, Yoshihiro Hagiwara, Eiji Itoi, Toshimi Aizawa, Masahiro Tsuchiya, Naoki Suzuki, Masashi Aoki, Makoto Kanzaki

    Scientific reports　12　(1)　14291-14291　2022/08/22

    DOI： 10.1038/s41598-022-18190-z 　

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    The physiological significance of skeletal muscle as a secretory organ is now well known but we can only speculate as to the existence of as-yet-unidentified myokines, especially those upregulated in response to muscle contractile activity. We first attempted to establish an "insert-chamber based in vitro exercise model" allowing the miniature but high cell-density culture state enabling highly developed contractile human myotubes to be readily obtained by applying electric pulse stimulation (EPS). By employing this in vitro exercise model, we identified R-spondin 3 (RSPO3) as a novel contraction-inducible myokine produced by cultured human myotubes. Contraction-dependent muscular RSPO3 mRNA upregulation was confirmed in skeletal muscles of mice subjected to sciatic nerve mediated in situ contraction as well as those of mice after 2 h of running. Pharmacological in vitro experiments demonstrated a relatively high concentration of metformin (millimolar range) to suppress the contraction-inducible mRNA upregulation of human myokines including RSPO3, interleukin (IL)-6, IL-8 and CXCL1. Our data also suggest human RSPO3 to be a paracrine factor that may positively participate in the myogenesis processes of myoblasts and satellite cells. Thus, the "insert chamber-based in vitro exercise model" is a potentially valuable research tool for investigating contraction-inducible biological responses of human myotubes usually exhibiting poorer contractility development even in the setting of EPS treatment.

  19. Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy. International-journal

    Naoki Suzuki, Ayumi Nishiyama, Hitoshi Warita, Masashi Aoki

    Journal of human genetics　2022/06/13

    DOI： 10.1038/s10038-022-01055-8 　

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    Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing on SOD1, fused in sarcoma (FUS), and transacting response DNA-binding protein. The frequency of the C9ORF72 mutation is low in Japan, unlike in Europe and the United States, while SOD1 and FUS are more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.

  20. Long-term outcomes after surgery to prevent aspiration for patients with amyotrophic lateral sclerosis. International-journal

    Temma Soga, Naoki Suzuki, Kengo Kato, Ai Kawamoto-Hirano, Yuko Kawauchi, Rumiko Izumi, Masaya Toyoshima, Shio Mitsuzawa, Tomomi Shijo, Kensuke Ikeda, Hitoshi Warita, Yukio Katori, Masashi Aoki, Masaaki Kato

    BMC neurology　22　(1)　94-94　2022/03/16

    DOI： 10.1186/s12883-022-02619-z 　

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    BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons selectively. In particular, weakness in respiratory and swallowing muscles occasionally causes aspiration pneumonia and choking, which can be lethal. Surgery to prevent aspiration, which separates the trachea and esophagus, can reduce the associated risks. Central-part laryngectomy (CPL) is a relatively minimally invasive surgery to prevent aspiration. No studies have been conducted on the long-term outcomes of surgery to prevent aspiration in patients with ALS. This case series aimed to determine the long-term outcomes of surgery to prevent aspiration and the use of a continuous low-pressure aspirator in patients with ALS by evaluating the frequency of intratracheal sputum suctions performed per day, intra- and postoperative complications, oral intake data, and satisfaction of patients and their primary caregiver to predict improvement in patients' quality of life (QOL). METHODS: We report a case series of six patients with ALS who underwent CPL along with tracheostomy to prevent aspiration between January 2015 and November 2018. We evaluated their pre- and postoperative status and administered questionnaires at the time of last admission to the patients and their primary caregivers. RESULTS: The mean follow-up period after CPL was 33.5 months. Aerophagia was a common postoperative complication. The use of a continuous low-pressure aspirator resulted in reduced frequency of intratracheal sputum suctions. All cases avoided aspiration pneumonia. Oral intake was continued for 2-4 years after the tracheostomy and CPL. The satisfaction levels of the patient and primary caregiver were high. CONCLUSION: Our case series suggests that the use of a continuous low-pressure aspirator in patients undergoing CPL improves oral intake and reduces the frequency of intratracheal sputum suctions, which improves the QOL of patients with ALS and their families and caregivers. CPL and continuous low-pressure aspiration should be considered as a management option for ALS with significant bulbar and respiratory muscle weakness/dysfunction.

  21. Feeder-supported in vitro exercise model using human satellite cells from patients with sporadic inclusion body myositis. International-journal

    Yuqing Li, Weijian Chen, Kazumi Ogawa, Masashi Koide, Tadahisa Takahashi, Yoshihiro Hagiwara, Eiji Itoi, Toshimi Aizawa, Masahiro Tsuchiya, Rumiko Izumi, Naoki Suzuki, Masashi Aoki, Makoto Kanzaki

    Scientific reports　12　(1)　1082-1082　2022/01/20

    DOI： 10.1038/s41598-022-05029-w 　

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    Contractile activity is a fundamental property of skeletal muscles. We describe the establishment of a "feeder-supported in vitro exercise model" using human-origin primary satellite cells, allowing highly-developed contractile myotubes to readily be generated by applying electrical pulse stimulation (EPS). The use of murine fibroblasts as the feeder cells allows biological responses to EPS in contractile human myotubes to be selectively evaluated with species-specific analyses such as RT-PCR. We successfully applied this feeder-supported co-culture system to myotubes derived from primary satellite cells obtained from sporadic inclusion body myositis (sIBM) patients who are incapable of strenuous exercise testing. Our results demonstrated that sIBM myotubes possess essentially normal muscle functions, including contractility development, de novo sarcomere formation, and contraction-dependent myokine upregulation, upon EPS treatment. However, we found that some of sIBM myotubes, but not healthy control myotubes, often exhibit abnormal cytoplasmic TDP-43 accumulation upon EPS-evoked contraction, suggesting potential pathogenic involvement of the contraction-inducible TDP-43 distribution peculiar to sIBM. Thus, our "feeder-supported in vitro exercise model" enables us to obtain contractile human-origin myotubes, potentially utilizable for evaluating exercise-dependent intrinsic and pathogenic properties of patient muscle cells. Our approach, using feeder layers, further expands the usefulness of the "in vitro exercise model".

  22. Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations. International-journal

    Shio Mitsuzawa, Naoki Suzuki, Tetsuya Akiyama, Mitsuru Ishikawa, Takefumi Sone, Jiro Kawada, Ryo Funayama, Matsuyuki Shirota, Hiroaki Mitsuhashi, Satoru Morimoto, Kensuke Ikeda, Tomomi Shijo, Akiyuki Ohno, Naoko Nakamura, Hiroya Ono, Risako Ono, Shion Osana, Tadashi Nakagawa, Ayumi Nishiyama, Rumiko Izumi, Shohei Kaneda, Yoshiho Ikeuchi, Keiko Nakayama, Teruo Fujii, Hitoshi Warita, Hideyuki Okano, Masashi Aoki

    Stem cell reports　16　(6)　1527-1541　2021/06/08

    DOI： 10.1016/j.stemcr.2021.04.021 　

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset incurable motor neuron (MN) disease. The reasons for selective MN vulnerability in ALS are unknown. Axonal pathology is among the earliest signs of ALS. We searched for novel modulatory genes in human MN axon shortening affected by TARDBP mutations. In transcriptome analysis of RNA present in the axon compartment of human-derived induced pluripotent stem cell (iPSC)-derived MNs, PHOX2B (paired-like homeobox protein 2B) showed lower expression in TARDBP mutant axons, which was consistent with axon qPCR and in situ hybridization. PHOX2B mRNA stability was reduced in TARDBP mutant MNs. Furthermore, PHOX2B knockdown reduced neurite length in human MNs. Finally, phox2b knockdown in zebrafish induced short spinal axons and impaired escape response. PHOX2B is known to be highly express in other types of neurons maintained after ALS progression. Collectively, TARDBP mutations induced loss of axonal resilience, which is an important ALS-related phenotype mediated by PHOX2B downregulation.

  23. Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT. International-journal

    Anthony A Amato, Michael G Hanna, Pedro M Machado, Umesh A Badrising, Hector Chinoy, Olivier Benveniste, Ananda Krishna Karanam, Min Wu, László B Tankó, Agnes Annette Schubert-Tennigkeit, Dimitris A Papanicolaou, Thomas E Lloyd, Merrilee Needham, Christina Liang, Katrina A Reardon, Marianne de Visser, Dana P Ascherman, Richard J Barohn, Mazen M Dimachkie, James A L Miller, John T Kissel, Björn Oskarsson, Nanette C Joyce, Peter Van den Bergh, Jonathan Baets, Jan L De Bleecker, Chafic Karam, William S David, Massimiliano Mirabella, Sharon P Nations, Hans H Jung, Elena Pegoraro, Lorenzo Maggi, Carmelo Rodolico, Massimiliano Filosto, Aziz I Shaibani, Kumaraswamy Sivakumar, Namita A Goyal, Madoka Mori-Yoshimura, Satoshi Yamashita, Naoki Suzuki, Masashi Aoki, Masahisa Katsuno, Hirokazu Morihata, Kenya Murata, Hiroyuki Nodera, Ichizo Nishino, Carla D Romano, Valerie S L Williams, John Vissing, Lixin Zhang Auberson

    Neurology　96　(12)　e1595-e1607　2021/03/23

    DOI： 10.1212/WNL.0000000000011626 　

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    OBJECTIVE: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). METHODS: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety. RESULTS: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). CONCLUSION: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02573467. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

  24. Hybrid Assistive Limb® for sporadic inclusion body myositis: A case series. International-journal

    Naoki Suzuki, Temma Soga, Rumiko Izumi, Masaya Toyoshima, Miwako Shibasaki, Itsumi Sato, Yu Kudo, Masashi Aoki, Masaaki Kato

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia　81　92-94　2020/11

    DOI： 10.1016/j.jocn.2020.09.031 　

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    We evaluated the efficacy of rehabilitation therapy with Hybrid Assistive Limb® (HAL; hereafter HAL therapy) in three patients diagnosed with sporadic inclusion body myositis (sIBM) who were hospitalized to undergo HAL therapy. Among them, one patient participated in eight courses and the other two in two courses of HAL therapy between 2017 and 2020. We determined the mean rate of improvement in two-minute walking distance and 6 m walking speed at the time of hospital discharge. After HAL therapy, we confirmed the patients' desire to continue the use of HAL. In one patient, we observed improvements of 146.0% and 120.0% in two-minute walk and 6 m walking speed, respectively, after the first course of HAL therapy; these values are 133.7% and 130% after the eighth course of HAL therapy. These values exceeded 90% in the other two patients after the second course of HAL therapy. HAL therapy maintained both quantity and quality of ambulation and showed positive psychological effects on patient conditions because it reduces exercise load and facilitates safety. While HAL therapy might be effective in maintaining and improving ambulation in patients with sIBM, we should consider to discontinue HAL therapy as it increased risk of falling.

  25. A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Ryoichi Nakamura, Kazuharu Misawa, Genki Tohnai, Masahiro Nakatochi, Sho Furuhashi, Naoki Atsuta, Naoki Hayashi, Daichi Yokoi, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Rina Hashimoto, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Yohei Okada, Tomohiko Ishihara, Osamu Onodera, Kenji Nakashima, Ryuji Kaji, Yoichiro Kamatani, Shiro Ikegawa, Yukihide Momozawa, Michiaki Kubo, Noriko Ishida, Naoko Minegishi, Masao Nagasaki, Gen Sobue

    Communications biology　3　(1)　526-526　2020/09/23

    DOI： 10.1038/s42003-020-01251-2 　

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    Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

  26. An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3. International-journal Peer-reviewed

    Yasuaki Watanabe, Tadashi Nakagawa, Tetsuya Akiyama, Makiko Nakagawa, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Keiko Nakayama

    iScience　23　(9)　101491-101491　2020/08/21

    DOI： 10.1016/j.isci.2020.101491 　

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    C21ORF2 and NEK1 have been identified as amyotrophic lateral sclerosis (ALS)-associated genes. Both genes are also mutated in certain ciliopathies, suggesting that they might contribute to the same signaling pathways. Here we show that FBXO3, the substrate receptor of an SCF ubiquitin ligase complex, binds and ubiquitylates C21ORF2, thereby targeting it for proteasomal degradation. C21ORF2 stabilizes the kinase NEK1, with the result that loss of FBXO3 stabilizes not only C21ORF2 but also NEK1. Conversely, NEK1-mediated phosphorylation stabilizes C21ORF2 by attenuating its interaction with FBXO3. We found that the ALS-associated V58L mutant of C21ORF2 is more susceptible to phosphorylation by NEK1, with the result that it is not ubiquitylated by FBXO3 and therefore accumulates together with NEK1. Expression of C21ORF2(V58L) in motor neurons induced from mouse embryonic stem cells impaired neurite outgrowth. We suggest that inhibition of NEK1 activity is a potential therapeutic approach to ALS associated with C21ORF2 mutation.

  27. Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases. International-journal Peer-reviewed

    Shinsuke Ishigaki, Yuichi Riku, Yusuke Fujioka, Kuniyuki Endo, Nobuyuki Iwade, Kaori Kawai, Minaka Ishibashi, Satoshi Yokoi, Masahisa Katsuno, Hirohisa Watanabe, Keiko Mori, Akio Akagi, Osamu Yokota, Seishi Terada, Ito Kawakami, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Mari Yoshida, Gen Sobue

    Brain : a journal of neurology　143　(8)　2398-2405　2020/08/01

    DOI： 10.1093/brain/awaa196 　

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    Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

  28. The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype-phenotype relationship and a hotspot on the inner DysF domain. International-journal Peer-reviewed

    Rumiko Izumi, Toshiaki Takahashi, Naoki Suzuki, Tetsuya Niihori, Hiroya Ono, Naoko Nakamura, Shinichi Katada, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki

    Human mutation　41　(9)　1540-1554　2020/05/12

    DOI： 10.1002/humu.24036 　

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    Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb-girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.

  29. AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy. International-journal Peer-reviewed

    Hiroya Ono, Naoki Suzuki, Shin-Ichiro Kanno, Genri Kawahara, Rumiko Izumi, Toshiaki Takahashi, Yasuo Kitajima, Shion Osana, Naoko Nakamura, Tetsuya Akiyama, Kensuke Ikeda, Tomomi Shijo, Shio Mitsuzawa, Ryoichi Nagatomi, Nobukazu Araki, Akira Yasui, Hitoshi Warita, Yukiko K Hayashi, Katsuya Miyake, Masashi Aoki

    Molecular therapy : the journal of the American Society of Gene Therapy　28　(4)　1133-1153　2020/04/08

    DOI： 10.1016/j.ymthe.2020.02.006 　

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    Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

  30. Prognosis of amyotrophic lateral sclerosis patients undergoing tracheostomy invasive ventilation therapy in Japan. International-journal Peer-reviewed

    Naoki Hayashi, Naoki Atsuta, Daichi Yokoi, Ryoichi Nakamura, Masahiro Nakatochi, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Akira Taniguchi, Mitsuya Morita, Osamu Kano, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Ikuko Aiba, Kouichi Mizoguchi, Masaya Oda, Ryuji Kaji, Gen Sobue

    Journal of neurology, neurosurgery, and psychiatry　91　(3)　285-290　2020/03

    DOI： 10.1136/jnnp-2019-322213 　

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    OBJECTIVE: The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy. METHODS: We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group. RESULTS: From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy. CONCLUSION: We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.

  31. Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5. International-journal

    Yoshitsugu Oikawa, Rumiko Izumi, Masashi Koide, Yoshihiro Hagiwara, Makoto Kanzaki, Naoki Suzuki, Koichi Kikuchi, Tetsuro Matsuhashi, Yukako Akiyama, Mariko Ichijo, Shun Watanabe, Takafumi Toyohara, Takehiro Suzuki, Eikan Mishima, Yasutoshi Akiyama, Yoshiaki Ogata, Chitose Suzuki, Hironori Hayashi, Eiichi N Kodama, Ken-Ichiro Hayashi, Eiji Itoi, Masashi Aoki, Shigeo Kure, Takaaki Abe

    PloS one　15　(12)　e0231064　2020

    DOI： 10.1371/journal.pone.0231064 　

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    Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

  32. Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy. International-journal Peer-reviewed

    Yasuo Kitajima, Naoki Suzuki, Kiyoshi Yoshioka, Rumiko Izumi, Maki Tateyama, Yoshitaka Tashiro, Ryosuke Takahashi, Masashi Aoki, Yusuke Ono

    Frontiers in cell and developmental biology　8　859-859　2020

    DOI： 10.3389/fcell.2020.00859 　

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    The ubiquitin-proteasome system has the capacity to degrade polyubiquitinated proteins and plays an important role in many cellular processes. However, the role of Rpt3, a crucial proteasomal gene, has not been investigated in adult muscles in vivo. Herein, we generated skeletal-muscle-specific Rpt3 knockout mice, in which genetic inactivation of Rpt3 could be induced by doxycycline administration. The Rpt3-knockout mice showed a significant reduction by more than 90% in the expression of Rpt3 in adult muscles. Using this model, we found that proteasome dysfunction in adult muscles resulted in muscle wasting and a decrease in the myofiber size. Immunoblotting analysis showed that the amounts of ubiquitinated proteins were markedly higher in muscles of Rpt3-deficient mice than in those of the control mice. Analysis of the autophagy pathway in the Rpt3-deficient mice showed that the upregulation of LC3II, p62, Atg5, Atg7, and Beclin-1 in protein levels, which supposed to be compensatory proteolysis activation. Our results suggest that the proteasome inhibition in adult muscle severely deteriorates myofiber integrity and results in muscle atrophy.

  33. Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS). International-journal Peer-reviewed

    Naoki Suzuki, Tetsuya Akiyama, Hitoshi Warita, Masashi Aoki

    Frontiers in neuroscience　14　194-194　2020

    DOI： 10.3389/fnins.2020.00194 　

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    Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

  34. Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity International-journal Peer-reviewed

    Yujiao Yu, Tadashi Nakagawa, Akane Morohoshi, Makiko Nakagawa, Noriko Ishida, Naoki Suzuki, Masashi Aoki, Keiko Nakayama

    HUMAN MOLECULAR GENETICS　28　(20)　3486-3497　2019/10

    DOI： 10.1093/hmg/ddz119 　

    ISSN： 0964-6906

    eISSN： 1460-2083

  35. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. International-journal Peer-reviewed

    Michael G Hanna, Umesh A Badrising, Olivier Benveniste, Thomas E Lloyd, Merrilee Needham, Hector Chinoy, Masashi Aoki, Pedro M Machado, Christina Liang, Katrina A Reardon, Marianne de Visser, Dana P Ascherman, Richard J Barohn, Mazen M Dimachkie, James A L Miller, John T Kissel, Björn Oskarsson, Nanette C Joyce, Peter Van den Bergh, Jonathan Baets, Jan L De Bleecker, Chafic Karam, William S David, Massimiliano Mirabella, Sharon P Nations, Hans H Jung, Elena Pegoraro, Lorenzo Maggi, Carmelo Rodolico, Massimiliano Filosto, Aziz I Shaibani, Kumaraswamy Sivakumar, Namita A Goyal, Madoka Mori-Yoshimura, Satoshi Yamashita, Naoki Suzuki, Masahisa Katsuno, Kenya Murata, Hiroyuki Nodera, Ichizo Nishino, Carla D Romano, Valerie S L Williams, John Vissing, Lixin Zhang Auberson, Min Wu, Ana de Vera, Dimitris A Papanicolaou, Anthony A Amato

    The Lancet. Neurology　18　(9)　834-844　2019/09

    DOI： 10.1016/S1474-4422(19)30200-5 　

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    BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

  36. In vitro exercise model using contractile human and mouse hybrid myotubes. International-journal Peer-reviewed

    Weijian Chen, Mazvita R Nyasha, Masashi Koide, Masahiro Tsuchiya, Naoki Suzuki, Yoshihiro Hagiwara, Masashi Aoki, Makoto Kanzaki

    Scientific reports　9　(1)　11914-11914　2019/08/15

    DOI： 10.1038/s41598-019-48316-9 　

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    Contraction of cultured myotubes with application of electric pulse stimulation (EPS) has been utilized for investigating cellular responses associated with actual contractile activity. However, cultured myotubes derived from human subjects often exhibit relatively poor EPS-evoked contractile activity, resulting in minimal contraction-inducible responses (i.e. myokine secretion). We herein describe an "in vitro exercise model", using hybrid myotubes comprised of human myoblasts and murine C2C12 myoblasts, exhibiting vigorous contractile activity in response to EPS. Species-specific analyses including RT-PCR and the BioPlex assay allowed us to separately evaluate contraction-inducible gene expressions and myokine secretions from human and mouse constituents of hybrid myotubes. The hybrid myotubes, half of which had arisen from primary human satellite cells obtained from biopsy samples, exhibited remarkable increases in the secretions of human cytokines (myokines) including interleukins (IL-6, IL-8, IL-10, and IL16), CXC chemokines (CXCL1, CXCL2, CXCL5, CXCL6, CXCL10), CC chemokines (CCL1, CCL2, CCL7, CCL8, CCL11, CCL13, CCL16, CCL17, CCL19, CCL20, CCL21, CCL22, CCL25, CCL27), and IFN-γ in response to EPS-evoked contractile activity. Together, these results indicate that inadequacies arising from human muscle cells are effectively overcome by fusing them with murine C2C12 cells, thereby supporting the development of contractility and the resulting cellular responses of human-origin muscle cells. Our approach, using hybrid myotubes, further expands the usefulness of the "in vitro exercise model".

  37. Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. International-journal Peer-reviewed

    Tetsuya Akiyama, Naoki Suzuki, Mitsuru Ishikawa, Koki Fujimori, Takefumi Sone, Jiro Kawada, Ryo Funayama, Fumiyoshi Fujishima, Shio Mitsuzawa, Kensuke Ikeda, Hiroya Ono, Tomomi Shijo, Shion Osana, Matsuyuki Shirota, Tadashi Nakagawa, Yasuo Kitajima, Ayumi Nishiyama, Rumiko Izumi, Satoru Morimoto, Yohei Okada, Takayuki Kamei, Mayumi Nishida, Masahiro Nogami, Shohei Kaneda, Yoshiho Ikeuchi, Hiroaki Mitsuhashi, Keiko Nakayama, Teruo Fujii, Hitoshi Warita, Hideyuki Okano, Masashi Aoki

    EBioMedicine　45　362-378　2019/07

    DOI： 10.1016/j.ebiom.2019.06.013 　

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    BACKGROUND: The characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated. METHOD: Two sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs possessing the single amino acid difference (p.H517D) in the fused in sarcoma (FUS) were constructed. By combining MN reporter lentivirus, MN specific phenotype was analyzed. Moreover, RNA profiling of isolated axons were conducted by applying the microfluidic devices that enable axon bundles to be produced for omics analysis. The relationship between the target gene, which was identified as a pathological candidate in ALS with RNA-sequencing, and the MN phenotype was confirmed by intervention with si-RNA or overexpression to hiPSCs-derived MNs and even in vivo. The commonality was further confirmed with other ALS-causative mutant hiPSCs-derived MNs and human pathology. FINDINGS: We identified aberrant increasing of axon branchings in FUS-mutant hiPSCs-derived MN axons compared with isogenic controls as a novel phenotype. We identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. The commonality of those phenotypes was further confirmed with other ALS causative mutation than FUS. INTERPRETATION: Analyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching. FUND: Japan Agency for Medical Research and development; Japanese Ministry of Education, Culture, Sports, Science and Technology Clinical Research, Innovation and Education Center, Tohoku University Hospital; Japan Intractable Diseases (Nanbyo) Research Foundation; the Kanae Foundation for the Promotion of Medical Science; and "Inochi-no-Iro" ALS research grant.

  38. The updated retrospective questionnaire study of sporadic inclusion body myositis in Japan. International-journal Peer-reviewed

    Naoki Suzuki, Madoka Mori-Yoshimura, Satoshi Yamashita, Satoshi Nakano, Ken-Ya Murata, Megumi Mori, Yukie Inamori, Naoko Matsui, En Kimura, Hirofumi Kusaka, Tomoyoshi Kondo, Hidefumi Ito, Itsuro Higuchi, Akihiro Hashiguchi, Hiroyuki Nodera, Ryuji Kaji, Maki Tateyama, Rumiko Izumi, Hiroya Ono, Masaaki Kato, Hitoshi Warita, Toshiaki Takahashi, Ichizo Nishino, Masashi Aoki

    Orphanet journal of rare diseases　14　(1)　155-155　2019/06/26

    DOI： 10.1186/s13023-019-1122-5 　

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    BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent muscle disease in elderly people, affecting the daily activities. sIBM is progressive with unknown cause and without effective treatment. In 2015, sIBM was classified as an intractable disease by the Japanese government, and the treatment cost was partly covered by the government. This study aimed to examine the changes in the number of patients with sIBM over the last 10 years and to elucidate the cross-sectional profile of Japanese patients with sIBM. METHODS: The number of sIBM patients was estimated through a reply-paid postcard questionnaire for attending physicians. Only patients diagnosed as "definite" or "probable" sIBM by clinical and biopsy sIBM criteria were included in this study (Lancet Neurol 6:620-631, 2007, Neuromuscul Disord 23:1044-1055, 2013). Additionally, a registered self-administered questionnaire was also sent to 106 patients who agreed to reply via their attending physician, between November 2016 and March 2017. RESULTS: The number of patients diagnosed with sIBM for each 5-year period was 286 and 384 in 2011 and 2016, respectively. Inability to stand-up, cane-dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair-bound should be included as sIBM milestones. Eight patients were positive for anti-hepatitis C virus antibody; three of them were administered interferon before sIBM onset. Steroids were administered to 33 patients (31.1%) and intravenous immunoglobulin to 46 patients (43.4%). From 2016 to 2017, total of 70 patients applied for the designated incurable disease medical expenses subsidy program. Although the treatment cost was partly covered by the government, many patients expressed psychological/mental and financial anxieties. CONCLUSIONS: We determined the cross-sectional profile of Japanese patients with sIBM. Continuous support and prospective surveys are warranted.

  39. The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells. International-journal Peer-reviewed

    Yasuo Kitajima, Naoki Suzuki, Aki Nunomiya, Shion Osana, Kiyoshi Yoshioka, Yoshitaka Tashiro, Ryosuke Takahashi, Yusuke Ono, Masashi Aoki, Ryoichi Nagatomi

    Stem cell reports　11　(6)　1523-1538　2018/12/11

    DOI： 10.1016/j.stemcr.2018.10.009 　

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    Adult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice lacking the crucial proteasomal component, Rpt3. Ablation of Rpt3 in satellite cells decreased proteasome activity. Proteasome dysfunction in Rpt3-deficient satellite cells impaired their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. We found that inactivation of proteasomal activity induced proliferation defects and apoptosis in satellite cells. Mechanistically, insufficient proteasomal activity upregulated the p53 pathway, which caused cell-cycle arrest. Our findings delineate a critical function of the proteasome system in maintaining satellite cells in adult muscle.

  40. Phase I clinical trial results of aceneuramic acid for GNE myopathy in Japan

    Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Rumiko Izumi, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Akifumi Suzuki, Takuhiro Yamaguchi, Ichizo Nishino, Masashi Aoki

    Translational Medicine Communications　3　(1)　2018/12

    Publisher: Springer Nature

    DOI： 10.1186/s41231-018-0025-0 　

    eISSN： 2396-832X

  41. Aberrant astrocytic expression of chondroitin sulfate proteoglycan receptors in a rat model of amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Tomomi Shijo, Hitoshi Warita, Naoki Suzuki, Yasuo Kitajima, Kensuke Ikeda, Tetsuya Akiyama, Hiroya Ono, Shio Mitsuzawa, Ayumi Nishiyama, Rumiko Izumi, Masashi Aoki

    Journal of neuroscience research　96　(2)　222-233　2018/02

    DOI： 10.1002/jnr.24127 　

    ISSN： 0360-4012

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    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive and systemic loss of motor neurons with gliosis in the central nervous system (CNS) is a neuropathological hallmark of ALS. Chondroitin sulfate proteoglycans (CSPGs) are the major components of the extracellular matrix of the mammalian CNS, and they inhibit axonal regeneration physically by participating to form the glial scar. Recently, protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related protein were discovered as CSPG receptors that play roles in inhibiting regeneration. Here we examined the expression of CSPG receptors in transgenic female rats overexpressing an ALS-linked mutant cytosolic Cu/Zn superoxide dismutase gene (SOD1). In contrast to controls, multiple immunofluorescence analyses revealed aberrant expression of CSPG receptors dominantly in reactive astrocytes, while PTPσ expression in neurons decreased in the spinal ventral horns of ALS transgenic rats. The aberrant and progressive astrocytic expression of CSPG receptors and reactive astrocytes themselves may be therapeutic targets for reconstructing a regeneration-supportive microenvironment under neurodegenerative conditions such as ALS.

  42. Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Ayumi Nishiyama, Tetsuya Niihori, Hitoshi Warita, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Naoki Suzuki, Yoko Aoki, Masashi Aoki

    Neurobiology of aging　53　194.e1-194.e8-194.e8　2017/05

    DOI： 10.1016/j.neurobiolaging.2017.01.004 　

    ISSN： 0197-4580

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients. A novel likely pathogenic homozygous variant in ALS2 was identified in 1 patient. In addition, 18 patients harbored 1-3 novel variants of uncertain significance, whereas hexanucleotide repeat expansions in C9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG, and OPTN variants were 32%, 11%, 2%, 2%, 1%, and 1%, respectively. These findings indicate considerable differences in the genetic variations associated with familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted.

  43. Pathomechanisms of anti-cytosolic 5'-nucleotidase 1A autoantibodies in sporadic inclusion body myositis. International-journal Peer-reviewed

    Nozomu Tawara, Satoshi Yamashita, Xiao Zhang, Mai Korogi, Ziwei Zhang, Tsukasa Doki, Yoshimasa Matsuo, Shunya Nakane, Yasushi Maeda, Kazuma Sugie, Naoki Suzuki, Masashi Aoki, Yukio Ando

    Annals of neurology　81　(4)　512-525　2017/04

    DOI： 10.1002/ana.24919 　

    ISSN： 0364-5134

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    OBJECTIVE: Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5'-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis. METHODS: We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies. RESULTS: Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A-positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the autoantibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A-positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A-positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration. INTERPRETATION: Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. Ann Neurol 2017;81:512-525.

  44. Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging. International-journal Peer-reviewed

    Feng Tian, Wenlong Yang, Daniel A Mordes, Jin-Yuan Wang, Johnny S Salameh, Joanie Mok, Jeannie Chew, Aarti Sharma, Ester Leno-Duran, Satomi Suzuki-Uematsu, Naoki Suzuki, Steve S Han, Fa-Ke Lu, Minbiao Ji, Rosanna Zhang, Yue Liu, Jack Strominger, Neil A Shneider, Leonard Petrucelli, X Sunney Xie, Kevin Eggan

    Nature communications　7　13283-13283　2016/10/31

    DOI： 10.1038/ncomms13283 　

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    The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics.

  45. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. International-journal Peer-reviewed

    Aaron Burberry, Naoki Suzuki, Jin-Yuan Wang, Rob Moccia, Daniel A Mordes, Morag H Stewart, Satomi Suzuki-Uematsu, Sulagna Ghosh, Ajay Singh, Florian T Merkle, Kathryn Koszka, Quan-Zhen Li, Leonard Zon, Derrick J Rossi, Jennifer J Trowbridge, Luigi D Notarangelo, Kevin Eggan

    Science translational medicine　8　(347)　347ra93　2016/07/13

    DOI： 10.1126/scitranslmed.aaf6038 　

    ISSN： 1946-6234

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    C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. We show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wild-type mouse bone marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity.

  46. SLC52A3, A Brown-Vialetto-van Laere syndrome candidate gene is essential for mouse development, but dispensable for motor neuron differentiation. International-journal Peer-reviewed

    Atsushi Intoh, Naoki Suzuki, Kathryn Koszka, Kevin Eggan

    Human molecular genetics　25　(9)　1814-23　2016/05/01

    DOI： 10.1093/hmg/ddw053 　

    ISSN： 0964-6906

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    Riboflavin, also known as vitamin B2, is essential for cellular reduction-oxidation reactions, but is not readily synthesized by mammalian cells. It has been proposed that riboflavin absorption occurs through solute carrier family 52 members (SLC52) A1, A2 and A3. These transporters are also candidate genes for the childhood onset-neural degenerative syndrome Brown-Vialetto-Van Laere (BVVL). Although riboflavin is an essential nutrient, why mutations in its transporters result in a neural cell-specific disorder remains unclear. Here, we provide evidence that Slc52a3 is the mouse ortholog of SLC52A3 and show that Slc52a3 deficiency results in early embryonic lethality. Loss of mutant embryos was associated with both defects in placental formation and increased rates of apoptosis in embryonic cells. In contrast, Slc52a3 -/- embryonic stem cell lines could be readily established and differentiated into motor neurons, suggesting that this transporter is dispensable for neural differentiation and short-term maintenance. Consistent with this finding, examination of Slc52a3 gene products in adult tissues revealed expression in the testis and intestine but little or none in the brain and spinal cord. Our results suggest that BVVL patients with SCL52A3 mutations may be good candidates for riboflavin replacement therapy and suggests that either the mutations these individuals carry are hypomorphic, or that in these cases alternative transporters act during human embryogenesis to allow full-term development.

  47. Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells. International-journal Peer-reviewed

    Naoki Ichiyanagi, Koki Fujimori, Masato Yano, Chikako Ishihara-Fujisaki, Takefumi Sone, Tetsuya Akiyama, Yohei Okada, Wado Akamatsu, Takuya Matsumoto, Mitsuru Ishikawa, Yoshinori Nishimoto, Yasuharu Ishihara, Tetsushi Sakuma, Takashi Yamamoto, Hitomi Tsuiji, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Hideyuki Okano

    Stem cell reports　6　(4)　496-510　2016/04/12

    DOI： 10.1016/j.stemcr.2016.02.011 　

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    Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.

  48. Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Toshiaki Takahashi, Naoki Suzuki, Maki Tateyama, Chigusa Watanabe, Kazuma Sugie, Hirotaka Nakanishi, Gen Sobue, Masaaki Kato, Hitoshi Warita, Yoko Aoki, Masashi Aoki

    Neurology. Genetics　1　(4)　e36　2015/12

    DOI： 10.1212/NXG.0000000000000036 　

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    OBJECTIVE: To investigate the genetic causes of suspected dysferlinopathy and to reveal the genetic profile for myopathies with dysferlin deficiency. METHODS: Using next-generation sequencing, we analyzed 42 myopathy-associated genes, including DYSF, in 64 patients who were clinically or pathologically suspected of having dysferlinopathy. Putative pathogenic mutations were confirmed by Sanger sequencing. In addition, copy-number variations in DYSF were investigated using multiplex ligation-dependent probe amplification. We also analyzed the genetic profile for 90 patients with myopathy with dysferlin deficiency, as indicated by muscle specimen immunohistochemistry, including patients from a previous cohort. RESULTS: We identified putative pathogenic mutations in 38 patients (59% of all investigated patients). Twenty-three patients had DYSF mutations, including 6 novel mutations. The remaining 16 patients, including a single patient who also carried the DYSF mutation, harbored putative pathogenic mutations in other genes. The genetic profile for 90 patients with dysferlin deficiency revealed that 70% had DYSF mutations (n = 63), 10% had CAPN3 mutations (n = 9), 2% had CAV3 mutations (n = 2), 3% had mutations in other genes (in single patients), and 16% did not have any identified mutations (n = 14). CONCLUSIONS: This study clarified the heterogeneous genetic profile for myopathies with dysferlin deficiency. Our results demonstrate the importance of a comprehensive analysis of related genes in improving the genetic diagnosis of dysferlinopathy as one of the most common subtypes of limb-girdle muscular dystrophy. Unresolved diagnoses should be investigated using whole-genome or whole-exome sequencing.

  49. Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation Peer-reviewed

    Rumiko Izumi, Hitoshi Warita, Tetsuya Niihori, Toshiaki Takahashi, Maki Tateyama, Naoki Suzuki, Ayumi Nishiyama, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Satomi Mitsuhashi, Ichizo Nishino, Yoko Aoki, Masashi Aoki

    NEUROLOGY-GENETICS　1　(3)　2015/10

    DOI： 10.1212/NXG.0000000000000023 　

    ISSN： 2376-7839

  50. FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Hitoshi Warita, Masaaki Kato, Hideki Mizuno, Naoko Shimakura, Tetsuya Akiyama, Hirokazu Furuya, Toshihiro Hokonohara, Akiko Iwaki, Shinji Togashi, Hidehiko Konno, Yasuto Itoyama

    Journal of human genetics　60　(10)　653-4　2015/10

    DOI： 10.1038/jhg.2015.93 　

  51. Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation. International-journal Peer-reviewed

    Rumiko Izumi, Hitoshi Warita, Tetsuya Niihori, Toshiaki Takahashi, Maki Tateyama, Naoki Suzuki, Ayumi Nishiyama, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Satomi Mitsuhashi, Ichizo Nishino, Yoko Aoki, Masashi Aoki

    Neurology. Genetics　1　(3)　e23-S280　2015/10

    Publisher: (一社)日本神経学会

    DOI： 10.1212/NXG.0000000000000023 　

    ISSN： 0009-918X

    eISSN： 1882-0654

  52. Proteasome dysfunction induces muscle growth defects and protein aggregation. International-journal Peer-reviewed

    Yasuo Kitajima, Yoshitaka Tashiro, Naoki Suzuki, Hitoshi Warita, Masaaki Kato, Maki Tateyama, Risa Ando, Rumiko Izumi, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Hidefumi Ito, Makoto Urushitani, Ryoichi Nagatomi, Ryosuke Takahashi, Masashi Aoki

    Journal of cell science　127　(Pt 24)　5204-17　2014/12/15

    DOI： 10.1242/jcs.150961 　

    ISSN： 0021-9533

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    The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes of protein and organelle clearance. The role of the proteasome pathway in mammalian muscle has not been examined in vivo. In this study, we report that the muscle-specific deletion of a crucial proteasomal gene, Rpt3 (also known as Psmc4), resulted in profound muscle growth defects and a decrease in force production in mice. Specifically, developing muscles in conditional Rpt3-knockout animals showed dysregulated proteasomal activity. The autophagy pathway was upregulated, but the process of autophagosome formation was impaired. A microscopic analysis revealed the accumulation of basophilic inclusions and disorganization of the sarcomeres in young adult mice. Our results suggest that appropriate proteasomal activity is important for muscle growth and for maintaining myofiber integrity in collaboration with autophagy pathways. The deletion of a component of the proteasome complex contributed to myofiber degeneration and weakness in muscle disorders that are characterized by the accumulation of abnormal inclusions.

  53. GNE myopathy associated with congenital thrombocytopenia: a report of two siblings. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Naoki Suzuki, Yoji Sasahara, Takeshi Rikiishi, Ayumi Nishiyama, Shuhei Nishiyama, Kaoru Endo, Masaaki Kato, Hitoshi Warita, Hidehiko Konno, Toshiaki Takahashi, Maki Tateyama, Takeshi Nagashima, Ryo Funayama, Keiko Nakayama, Shigeo Kure, Yoichi Matsubara, Yoko Aoki, Masashi Aoki

    Neuromuscular disorders : NMD　24　(12)　1068-72　2014/12

    DOI： 10.1016/j.nmd.2014.07.008 　

    ISSN： 0960-8966

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    GNE myopathy is an autosomal recessive muscular disorder caused by mutations in the gene encoding the key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we report two siblings with myopathy with rimmed vacuoles and congenital thrombocytopenia who harbored two compound heterozygous GNE mutations, p.V603L and p.G739S. Thrombocytopenia, which is characterized by shortened platelet lifetime rather than ineffective thrombopoiesis, has been observed since infancy. We performed exome sequencing and array CGH to identify the underlying genetic etiology of thrombocytopenia. No pathogenic variants were detected among the known causative genes of recessively inherited thrombocytopenia; yet, candidate variants in two genes that followed an autosomal recessive mode of inheritance, including previously identified GNE mutations, were detected. Alternatively, it is possible that the decreased activity of GNE/MNK itself, which would lead to decreased sialic content in platelets, is associated with thrombocytopenia in these patients. Further investigations are required to clarify the association between GNE myopathy and the pathogenesis of thrombocytopenia.

  54. Genetic validation of a therapeutic target in a mouse model of ALS. International-journal Peer-reviewed

    A Sophie de Boer, Kathryn Koszka, Evangelos Kiskinis, Naoki Suzuki, Brandi N Davis-Dusenbery, Kevin Eggan

    Science translational medicine　6　(248)　248ra104　2014/08/06

    DOI： 10.1126/scitranslmed.3009351 　

    ISSN： 1946-6234

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    Neurons produced from stem cells have emerged as a tool to identify new therapeutic targets for neurological diseases such as amyotrophic lateral sclerosis (ALS). However, it remains unclear to what extent these new mechanistic insights will translate to animal models, an important step in the validation of new targets. Previously, we found that glia from mice carrying the SOD1G93A mutation, a model of ALS, were toxic to stem cell-derived human motor neurons. We use pharmacological and genetic approaches to demonstrate that the prostanoid receptor DP1 mediates this glial toxicity. Furthermore, we validate the importance of this mechanism for neural degeneration in vivo. Genetic ablation of DP1 in SOD1G93A mice extended life span, decreased microglial activation, and reduced motor neuron loss. Our findings suggest that blocking DP1 may be a therapeutic strategy in ALS and demonstrate that discoveries from stem cell models of disease can be corroborated in vivo.

  55. The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. International-journal Peer-reviewed

    Naoki Suzuki, Asif M Maroof, Florian T Merkle, Kathryn Koszka, Atsushi Intoh, Ian Armstrong, Rob Moccia, Brandi N Davis-Dusenbery, Kevin Eggan

    Nature neuroscience　16　(12)　1725-7　2013/12

    DOI： 10.1038/nn.3566 　

    ISSN： 1097-6256

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    Using transgenic mice harboring a targeted LacZ insertion, we studied the expression pattern of the C9ORF72 mouse ortholog (3110043O21Rik). Unlike most genes that are mutated in amyotrophic lateral sclerosis (ALS), which are ubiquitously expressed, the C9ORF72 ortholog was most highly transcribed in the neuronal populations that are sensitive to degeneration in ALS and frontotemporal dementia. Thus, our results provide a potential explanation for the cell type specificity of neuronal degeneration caused by C9ORF72 mutations.

  56. Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure. International-journal Peer-reviewed

    Rumiko Izumi, Tetsuya Niihori, Yoko Aoki, Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Toshiaki Takahashi, Maki Tateyama, Takeshi Nagashima, Ryo Funayama, Koji Abe, Keiko Nakayama, Masashi Aoki, Yoichi Matsubara

    Journal of human genetics　58　(5)　259-66　2013/05

    DOI： 10.1038/jhg.2013.9 　

    ISSN： 1434-5161

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    Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. The major genetic basis of MFMs is unknown. In 1993, our group reported a Japanese family with dominantly inherited cytoplasmic body myopathy, which is now included in MFM, characterized by late-onset chronic progressive distal muscle weakness and early respiratory failure. In this study, we performed linkage analysis and exome sequencing on these patients and identified a novel c.90263G>T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.

  57. Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B. International-journal Peer-reviewed

    Toshiaki Takahashi, Masashi Aoki, Naoki Suzuki, Maki Tateyama, Chikako Yaginuma, Hitomi Sato, Miho Hayasaka, Hitomi Sugawara, Mariko Ito, Emi Abe-Kondo, Naoko Shimakura, Tohru Ibi, Satoshi Kuru, Tadashi Wakayama, Gen Sobue, Naoki Fujii, Toshio Saito, Tsuyoshi Matsumura, Itaru Funakawa, Eiichiro Mukai, Toru Kawanami, Mitsuya Morita, Mineo Yamazaki, Takashi Hasegawa, Jun Shimizu, Shoji Tsuji, Shigeki Kuzuhara, Hiroyasu Tanaka, Masaru Yoshioka, Hidehiko Konno, Hiroshi Onodera, Yasuto Itoyama

    Journal of neurology, neurosurgery, and psychiatry　84　(4)　433-40　2013/04

    DOI： 10.1136/jnnp-2011-301339 　

    ISSN： 0022-3050

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    OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

  58. FUS/TLS-immunoreactive neuronal and glial cell inclusions increase with disease duration in familial amyotrophic lateral sclerosis with an R521C FUS/TLS mutation. International-journal Peer-reviewed

    Naoki Suzuki, Shinsuke Kato, Masako Kato, Hitoshi Warita, Hideki Mizuno, Masaaki Kato, Naoko Shimakura, Haruhiko Akiyama, Zen Kobayashi, Hidehiko Konno, Masashi Aoki

    Journal of neuropathology and experimental neurology　71　(9)　779-88　2012/09

    DOI： 10.1097/NEN.0b013e318264f164 　

    ISSN： 0022-3069

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    Basophilic inclusions (BIs) are pathological features of a subset of frontotemporal lobar degeneration disorders, including sporadic amyotrophic lateral sclerosis (ALS) and familial ALS (FALS). Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have recently been identified as a cause of FALS. The FUS/TLS-immunoreactive inclusions are consistently found in cases of frontotemporal lobar degeneration with BIs; however, the association between ALS cases with BIs and FUS/TLS accumulation is not well understood. We used immunohistochemistry to analyze 3 autopsy cases of FALS with the FUS/TLS mutation and with BIs using anti-FUS/TLS antibodies. The disease durations were 1, 3, and 9 years. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions. As early as 1 year after the onset, BIs, neuronal cytoplasmic inclusions and glial cytoplasmic inclusions were found in the substantia nigra in addition to the anterior horn of the spinal cord. Glial cytoplasmic inclusions are found earlier and in a wider distribution than neuronal cytoplasmic inclusions. The distribution of FUS/TLS-immunoreactive inclusions in FUS/TLS-mutated FALS with BIs was broader than that of BIs alone, suggesting that the pathogenetic mechanism may have originated from the FUS/TLS proteinopathy.

  59. Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations. International-journal Peer-reviewed

    Madoka Mori-Yoshimura, Kazunari Monma, Naoki Suzuki, Masashi Aoki, Toshihide Kumamoto, Keiko Tanaka, Hiroyuki Tomimitsu, Satoshi Nakano, Masahiro Sonoo, Jun Shimizu, Kazuma Sugie, Harumasa Nakamura, Yasushi Oya, Yukiko K Hayashi, May Christine V Malicdan, Satoru Noguchi, Miho Murata, Ichizo Nishino

    Journal of the neurological sciences　318　(1-2)　100-5　2012/07/15

    DOI： 10.1016/j.jns.2012.03.016 　

    ISSN： 0022-510X

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    BACKGROUND: Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, also called distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM), is a rare, progressive autosomal recessive disorder caused by mutations in the GNE gene. Here, we examined the relationship between genotype and clinical phenotype in participants with GNE myopathy. METHODS: Participants with GNE myopathy were asked to complete a questionnaire regarding medical history and current symptoms. RESULTS: A total of 71 participants with genetically confirmed GNE myopathy (27 males and 44 females; mean age, 43.1±13.0 (mean±SD) years) completed the questionnaire. Initial symptoms (e.g., foot drop and lower limb weakness) appeared at a mean age of 24.8±8.3 years. Among the 71 participants, 11 (15.5%) had the ability to walk, with a median time to loss of ambulation of 17.0±2.1 years after disease onset. Participants with a homozygous mutation (p.V572L) in the N-acetylmannosamine kinase domain (KD/KD participants) had an earlier disease onset compared to compound heterozygous participants with mutations in the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase and N-acetylmannosamine kinase domains (ED/KD participants; 26.3±7.3 vs. 21.2±11.1 years, respectively). KD/KD participants were more frequently non-ambulatory compared to ED/KD participants at the time of survey (80% vs. 50%). Data were verified using medical records available from 17 outpatient participants. CONCLUSIONS: Homozygous KD/KD participants exhibited a more severe phenotype compared to heterozygous ED/KD participants.

  60. Increase in number of sporadic inclusion body myositis (sIBM) in Japan. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Madoka Mori-Yoshimura, Yukiko K Hayashi, Ikuya Nonaka, Ichizo Nishino

    Journal of neurology　259　(3)　554-6　2012/03

    DOI： 10.1007/s00415-011-6185-8 　

    ISSN： 0340-5354

  61. Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. International-journal Peer-reviewed

    Hidefumi Ito, Kengo Fujita, Masataka Nakamura, Reika Wate, Satoshi Kaneko, Shoichi Sasaki, Kiyomi Yamane, Naoki Suzuki, Masashi Aoki, Noriyuki Shibata, Shinji Togashi, Akihiro Kawata, Yoko Mochizuki, Toshio Mizutani, Hirofumi Maruyama, Asao Hirano, Ryosuke Takahashi, Hideshi Kawakami, Hirofumi Kusaka

    Acta neuropathologica　121　(4)　555-7　2011/04

    DOI： 10.1007/s00401-011-0809-z 　

    ISSN： 0001-6322

  62. Feasibility study for functional test battery of SOD transgenic rat (H46R) and evaluation of edaravone, a free radical scavenger. International-journal Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Hideki Mizuno, Naoki Suzuki, Satoshi Yuki, Yasuto Itoyama

    Brain research　1382　321-5　2011/03/25

    DOI： 10.1016/j.brainres.2011.01.058 　

    ISSN： 0006-8993

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    We evaluated a battery of functional tests for investigating the effects of edaravone, a free radical scavenger, in SOD1 transgenic (H46R) rat model of amyotrophic lateral sclerosis. Edaravone (1.5 or 3.0mg/kg/h) or saline was administered intravenously to rats by continuous infusion (1h per day) for 2days, followed by a 2-day holiday. Lifetime and duration of illness were evaluated, and motor function was assessed using the hind-foot reflex test, landing foot-splay test, rota rod test and inclined plate test at a predetermined time point at which half of the control animals had died. Statistical comparison of motor functions of edaravone-treated and control SOD1 transgenic rats at an objectively determined time point was confirmed to be feasible. Edaravone-treated male rats showed significantly better performance in the landing foot-splay test. The present model seems suitable for evaluating motor function of H46R SOD1 transgenic rats, and be useful for examining the therapeutic potential of edaravone to treat amyotrophic lateral sclerosis.

  63. Mutations of optineurin in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Hirofumi Maruyama, Hiroyuki Morino, Hidefumi Ito, Yuishin Izumi, Hidemasa Kato, Yasuhito Watanabe, Yoshimi Kinoshita, Masaki Kamada, Hiroyuki Nodera, Hidenori Suzuki, Osamu Komure, Shinya Matsuura, Keitaro Kobatake, Nobutoshi Morimoto, Koji Abe, Naoki Suzuki, Masashi Aoki, Akihiro Kawata, Takeshi Hirai, Takeo Kato, Kazumasa Ogasawara, Asao Hirano, Toru Takumi, Hirofumi Kusaka, Koichi Hagiwara, Ryuji Kaji, Hideshi Kawakami

    Nature　465　(7295)　223-6　2010/05/13

    DOI： 10.1038/nature08971 　

    ISSN： 0028-0836

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    Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.

  64. Neuromyelitis optica preceded by hyperCKemia episode. Peer-reviewed

    Suzuki N, Takahashi T, Aoki M, Misu T, Konohana S, Okumura T, Takahashi H, Kameya S, Yamaki K, Kumagai T, Fujihara K, Itoyama Y

    Neurology　74　1543-1545　2010/05

    DOI： 10.1212/WNL.0b013e3181dd445b. 　

  65. FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Hitoshi Warita, Masaaki Kato, Hideki Mizuno, Naoko Shimakura, Tetsuya Akiyama, Hirokazu Furuya, Toshihiro Hokonohara, Akiko Iwaki, Shinji Togashi, Hidehiko Konno, Yasuto Itoyama

    Journal of human genetics　55　(4)　252-4　2010/04

    DOI： 10.1038/jhg.2010.16 　

    ISSN： 1434-5161

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    Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases.

  66. A case of McArdle disease: efficacy of vitamin B6 on fatigability and impaired glycogenolysis. Peer-reviewed

    Rumiko Izumi, Naoki Suzuki, Kazuhiro Kato, Hitoshi Warita, Maki Tateyama, Ichiro Nakashima, Yasuto Itoyama

    Internal medicine (Tokyo, Japan)　49　(15)　1623-5　2010

    DOI： 10.2169/internalmedicine.49.3525 　

    ISSN： 0918-2918

    eISSN： 1349-7235

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    McArdle disease is a glycogenetic myopathy caused by a deficit of myophosphorylase inherited in an autosomal recessive pattern. Here, we report a case of McArdle disease in which fatigability was the only subjective complaint. Objective neurological findings were normal except for very mild muscle weakness in limbs and an elevated serum creatine kinase level. Ischemic forearm exercise test showed deficient glycogenolysis. In the muscle biopsy specimen, periodic acid Schiff (PAS) stained subsarcolemmal glycogen was increased and the muscle phosphorylase A activity was decreased. After administration of vitamin B6, fatigability was diminished and ischemic forearm exercise test showed improved glycogenolysis. Vitamin B6 may be beneficial for McArdle disease, especially for its easy fatigability.

  67. A CASE OF NMO SEROPOSITIVE FOR AQUAPORIN-4 ANTIBODY MORE THAN 10 YEARS BEFORE ONSET Peer-reviewed

    S. Nishiyama, T. Ito, T. Misu, T. Takahashi, A. Kikuchi, N. Suzuki, K. Jin, M. Aoki, K. Fujihara, Y. Itoyama

    NEUROLOGY　72　(22)　1960-1961　2009/06

    DOI： 10.1212/WNL.0b013e3181a82621 　

    ISSN： 0028-3878

  68. PROCALCITONIN MIGHT HELP IN DISCRIMINATION BETWEEN MENINGEAL NEURO-BEHCET DISEASE AND BACTERIAL MENINGITIS Peer-reviewed

    N. Suzuki, H. Mizuno, M. Nezu, Y. Takai, T. Misu, H. Kuroda, M. Aoki, I. Nakashima, Y. Itoyama

    NEUROLOGY　72　(8)　762-763　2009/02

    DOI： 10.1212/01.wnl.0000343046.88848.76 　

    ISSN： 0028-3878

  69. NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS. International-journal Peer-reviewed

    Naoki Suzuki, Norio Motohashi, Akiyoshi Uezumi, So-ichiro Fukada, Tetsuhiko Yoshimura, Yasuto Itoyama, Masashi Aoki, Yuko Miyagoe-Suzuki, Shin'ichi Takeda

    The Journal of clinical investigation　117　(9)　2468-76　2007/09

    DOI： 10.1172/JCI30654 　

    ISSN： 0021-9738

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    Forkhead box O (Foxo) transcription factors induce muscle atrophy by upregulating the muscle-specific E3 ubiquitin ligases MuRF-1 and atrogin-1/MAFbx, but other than Akt, the upstream regulators of Foxos during muscle atrophy are largely unknown. To examine the involvement of the dystrophin glycoprotein complex (DGC) in regulation of Foxo activities and muscle atrophy, we analyzed the expression of DGC members during tail suspension, a model of unloading-induced muscle atrophy. Among several DGC members, only neuronal NOS (nNOS) quickly dislocated from the sarcolemma to the cytoplasm during tail suspension. Electron paramagnetic resonance spectrometry revealed production of NO in atrophying muscle. nNOS-null mice showed much milder muscle atrophy after tail suspension than did wild-type mice. Importantly, nuclear accumulation of dephosphorylated Foxo3a was not evident in nNOS-null muscle, and neither MuRF-1 nor atrogin-1/MAFbx were upregulated during tail suspension. Furthermore, an nNOS-specific inhibitor, 7-nitroindazole, significantly prevented suspension-induced muscle atrophy. The NF-kappaB pathway was activated in both wild-type and nNOS-null muscle during tail suspension. We also show that nNOS was involved in the mechanism of denervation-induced atrophy. We conclude that nNOS/NO mediates muscle atrophy via regulation of Foxo transcription factors and is a new therapeutic target for disuse-induced muscle atrophy.

  70. Late-onset distal myopathy with rimmed vacuoles without mutation in the GNE or dysferlin genes. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Hideki Mizuno, Yoshiaki Onodera, Toshiaki Takahashi, Tetsuya Nagata, Maki Tateyama, Yasuto Itoyama

    Muscle & nerve　32　(6)　812-4　2005/12

    DOI： 10.1002/mus.20417 　

    ISSN： 0148-639X

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    We report two brothers from a Japanese family with a late-onset distal myopathy characterized by rimmed vacuoles and dysferlin deficiency with no inflammatory infiltration and dystrophic changes in muscle biopsy. Mutations in the GNE, dysferlin, caveolin 3, emerin, and lamin A/C genes were excluded. We speculate that dysferlin is involved in the pathogenesis of the myopathy in these patients, which may represent a new disease entity presenting as a distal myopathy.

  71. Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease

    Hamaguchi, T., Kitamoto, T., Sato, T., Mizusawa, H., Nakamura, Y., Noguchi, M., Furukawa, Y., Ishida, C., Kuji, I., Mitani, K., Murayama, S., Kohriyama, T., Katayama, S., Yamashita, M., Yamamoto, T., Udaka, F., Kawakami, A., Ihara, Y., Nishinaka, T., Kuroda, S., Suzuki, N., Shiga, Y., Arai, H., Maruyama, M., Yamada, M.

    Neurology　64　(4)　2005

  72. Novel dysferlin mutations and characteristic muscle atrophy in late-onset Miyoshi myopathy. International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Toshiaki Takahashi, Daiki Takano, Masahiro Asano, Yusei Shiga, Yoshiaki Onodera, Maki Tateyama, Yasuto Itoyama

    Muscle & nerve　29　(5)　721-3　2004/05

    DOI： 10.1002/mus.20025 　

    ISSN： 0148-639X

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    Miyoshi myopathy is characterized by weakness of the calf muscles during early adulthood. We report a case of late-onset Miyoshi myopathy presenting at 48 years of age, with novel mutations in the dysferlin gene. Muscle computed tomography clearly revealed severe atrophy in the soleus and medial gastrocnemius muscles. Even older patients with atrophy in the posterior compartment of the distal lower extremities and a relatively high serum creatine kinase level should be examined for the dysferlin gene.

  73. Clinicopathological Features of Mixed Connective Tissue Disease-Related Myositis: A Case Series. International-journal

    Naohiro Sakamoto, Rumiko Izumi, Naoki Suzuki, Maki Tateyama, Masashi Aoki

    Muscle & nerve　71　(4)　583-592　2025/04

    DOI： 10.1002/mus.28360 　

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    INTRODUCTION: Mixed connective tissue disease (MCTD) patients often have myositis, however, myopathological and clinical data for MCTD are limited. Recent reports have shown that the pathology of MCTD myositis resembles that of immune-mediated necrotizing myopathy (IMNM), whereas earlier reports described perifascicular atrophy or inflammatory infiltrates predominantly in the perivascular region in MCTD myositis. We aim to describe the clinical and myopathological features of MCTD myositis. METHODS: We analyzed the clinical and myopathological findings of nine myositis patients with U1-RNP antibodies who fulfilled the diagnostic criteria for MCTD. RESULTS: Eight patients had muscle weakness in the proximal extremities, and overall, six patients had atypical weakness in the face, neck, wrist, or fingers. Four of those patients required additional intensive treatment (intravenous immunoglobulin or methylprednisolone). Therapeutic responses were consistently favorable overall, and there were no deaths during the observation period. In biopsied muscle specimens, common findings were mild myogenic change, increased necrotic and regenerating fibers, and inflammatory infiltrates predominating in the perivascular region. Two specimens were classified into the spectrum of dermatomyositis (DM); the remaining seven specimens, which had a smaller number of necrotic fibers and nonspecific infiltration, were unclassifiable. DISCUSSION: Patients with MCTD myositis often exhibit an axial or atypical distribution of muscle weakness, which may require intensive therapy. Histological study demonstrates the heterogeneity of myopathology of MCTD myositis and suggests that DM and underlying vasculopathy might be present in these patients.

  74. A Serial Assessment of T1 and T2 Mapping Cardiac Magnetic Resonance Before and After Heart Failure Onset in a Case of Cardiomyopathy in Anti-mitochondrial Antibody-positive Myositis.

    Mitsuru Ishizuka, Hideaki Suzuki, Satoshi Higuchi, Hidenobu Takagi, Naoki Suzuki, Rumiko Izumi, Hirofumi Watanabe, Haruka Sato, Taijyu Satoh, Saori Miyamichi-Yamamoto, Nobuhiro Yaoita, Kouki Takeuchi, Marina Arai, Hideka Hayashi, Kotaro Nochioka, Hiroyuki Takahama, Shunsuke Tatebe, Hiroshi Fujii, Masashi Aoki, Satoshi Yasuda

    Internal medicine (Tokyo, Japan)　2025/03/22

    DOI： 10.2169/internalmedicine.5007-24 　

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    A 69-year-old woman presented with heart failure and progressive muscle weakness and was diagnosed as anti-mitochondrial antibody (AMA) myositis with cardiac involvement. Immunosuppressive therapy with prednisolone and intravenous cyclophosphamide significantly improved the symptoms, hemodynamics, and cardiac function. Cardiac magnetic resonance (CMR) T1 and T2 mapping showed elevated native T1, T2, and extracellular volume fractions during heart failure exacerbation (day 37) compared to pre-hospitalization values (10 months before admission) and follow-up conducted 6 and 12 months after admission. This case underscores the importance of comprehensive evaluation, such as serial CMR imaging and immunosuppressive therapy, in managing myocardial involvement in AMA-positive myositis.

  75. Impacts of High-Intensity One-Year Respiratory Muscle Exercise on Respiratory Muscle Force and Dyspnea at Various Body Trunk Angles in a Tetraplegic Patient.

    Tatsuma Okazaki, Ryo Takahashi, Taruhi Matsui, Midori Miyagi, Takahiro Miura, Naoki Suzuki, Satoru Ebihara

    The Tohoku journal of experimental medicine　2025/03/13

    DOI： 10.1620/tjem.2025.J037 　

  76. Antisense oligonucleotide-mediated exon 27 skipping restores dysferlin function in dysferlinopathy patient-derived muscle cells International-journal

    Naoki Suzuki

    Molecular Therapy Nucleic Acids　36　(1)　102462-102462　2025/03

    DOI： 10.1016/j.omtn.2025.102462 　

  77. Inhibition of methionine aminopeptidase in C2C12 myoblasts disrupts cell integrity via increasing endoplasmic reticulum stress. International-journal

    Shion Osana, Cheng-Ta Tsai, Naoki Suzuki, Kazutaka Murayama, Masaki Kaneko, Katsuhiko Hata, Hiroaki Takada, Yutaka Kano, Ryoichi Nagatomi

    Biochimica et biophysica acta. Molecular cell research　1872　(3)　119901-119901　2025/01/13

    DOI： 10.1016/j.bbamcr.2025.119901 　

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    Proteasome-dependent protein degradation and the digestion of peptides by aminopeptidases are essential for myogenesis. Methionine aminopeptidases (MetAPs) are uniquely involved in, both, the proteasomal degradation of proteins and in the regulation of translation (via involvement in post-translational modification). Suppressing MetAP1 and MetAP2 expression inhibits the myogenic differentiation of C2C12 myoblasts. However, the molecular mechanism by which inhibiting MetAPs impairs cellular function remains to be elucidated. Here, we provide evidence for our hypothesis that MetAPs regulate proteostasis and that their inhibition increases ER stress by disrupting the post-translational modification, and thereby compromises cell integrity. Thus, using C2C12 myoblasts, we investigate the effect of inhibiting MetAPs on cell proliferation and the molecular mechanisms underpinning its effects. We found that exposure to bengamide B (a MetAP inhibitor) caused C2C12 myoblasts to lose their proliferative abilities via cell cycle arrest. The underlying mechanism involved the accumulation of abnormal proteins (due to the decrease in the N-terminal methionine removal function) which led to increased endoplasmic reticulum stress, decreased protein synthesis, and a protective activation of the autophagy pathway. To identify the MetAP involved in these effects, we use siRNAs to specifically knockdown MetAP1 and MetAP2 expressions. We found that only MetAP2 knockdown mimicked the effects seen with bengamide B treatment. Thus, we suggest that MetAP2, rather than MetAP1, is involved in maintaining the integrity of C2C12 myoblasts. Our results are useful in understanding muscle regeneration, obesity, and overeating disorders. It will help guide new treatment strategies for these disorders.

  78. Dopa-responsive parkinsonism without cerebellar ataxia in spinocerebellar ataxia 6. International-journal

    Shun Yoshida, Toshiyuki Takahashi, Naoki Suzuki, Muneshige Tobita

    Clinical parkinsonism & related disorders　12　100322-100322　2025

    DOI： 10.1016/j.prdoa.2025.100322 　

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    •While SCA6 patients mainly show pure cerebellar ataxia, some cases have parkinsonism.•In SCA6 patients, levodopa responsivity to parkinsonism is seldom reported.•We show an SCA6 patient with dopa-responsive parkinsonism without cerebellar ataxia.

  79. Impact of sex, age at onset, and anti-cN1A antibodies on sporadic inclusion body myositis. International-journal

    Satoshi Yamashita, Nozomu Tawara, Kazuma Sugie, Naoki Suzuki, Ichizo Nishino, Masashi Aoki

    Journal of the neurological sciences　464　123164-123164　2024/08/06

    DOI： 10.1016/j.jns.2024.123164 　

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    BACKGROUND: Inclusion body myositis (IBM) is a progressive myopathy occurring in patients over 45 years of age, with heterogeneous and variable clinical features. This study aimed to determine the influence of autoantibodies, gender, and age of onset on the clinical features of IBM. METHODS: Medical records and muscle histology findings of 570 participants with suspected IBM were reviewed. Various characteristics of patients who met the 2011 ENMC IBM diagnostic criteria were compared based on the presence of anti-cytosolic 5'-nucleotidase 1 A (cN1A) autoantibodies, gender, age of onset, and disease duration. RESULTS: Of the 353 patients who met the criteria, 41.6% were female. The mean age at onset was 64.6 ± 9.3 years, and the mean duration from onset to diagnosis was 5.7 ± 4.7 years. 196 of the 353 patients (55.5%) were positive for anti-cN1A autoantibodies and 157 were negative. Logistic regression showed that patients with anti-cN1A autoantibodies had a higher frequency of finger flexion weakness. Multiple regression showed that patients with later age of onset had shorter disease duration, lower BMI, and lower serum CK levels. Male patients had a higher frequency of onset with finger weakness and female patients had a lower BMI. CONCLUSION: Autoantibodies, gender, age of onset, and disease duration may influence the clinical presentation of IBM, highlighting the need for a precision medicine approach that considers these factors along with the underlying mechanisms of the disease.

  80. Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps. International-journal

    Rumiko Izumi, Hitoshi Warita, Tetsuya Niihori, Yoshihiko Furusawa, Misa Nakano, Yasushi Oya, Kazuhiro Kato, Takuro Shiga, Kensuke Ikeda, Naoki Suzuki, Ichizo Nishino, Yoko Aoki, Masashi Aoki

    Cerebellum (London, England)　23　(4)　1498-1508　2024/02/07

    DOI： 10.1007/s12311-024-01666-1 　

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    Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

  81. Gait Acquisition with a Quadrilateral Socket after Ultra-short Transfemoral Amputation because of Staphylococcal Toxic Shock Syndrome.

    Naoki Suzuki, Midori Miyagi, Yoshihito Furusawa, Takahiro Miura, Takumi Agarie, Yuki Imaizumi, Chihiro Nakazawa, Tamao Takahashi, Keisuke Obata, Yumi Izumiyama, Kazunori Nishijima, Hiroyuki Miyauchi, Naoya Iwata, Tomoe Sobu, Yusuke Sekiguchi, Kota Ataka, Kumiko Takahashi, Masashi Takeuchi, Tatsuma Okazaki, Satoru Ebihara

    Progress in rehabilitation medicine　9　20240036-20240036　2024

    DOI： 10.2490/prm.20240036 　

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    BACKGROUND: Streptococcal toxic shock syndrome (STSS) is a notifiable disease under Japan's Infectious Disease Control Law and has become a pandemic following COVID-19. STSS often leads to necrotizing fasciitis, with a mortality rate exceeding 30%. Even in surviving patients, limb amputations are common. CASE: A 39-year-old woman developed STSS. She underwent 18 surgeries and vacuum-assisted closure therapy, which resulted in ultra-short right transfemoral amputation. With a strong desire to walk again, she began fitting for a provisional prosthesis 3 months post-amputation. Given the preserved hip muscle strength, an ultra-short transfemoral prosthesis was selected over a hip disarticulation prosthesis. The key components included a plug-in quadrilateral socket, a belt used to suspend the transfemoral prosthesis, a hydraulic knee joint, and an energy-storing foot. She regained walking ability using crutches. To address pain and skin issues in the stump load-bearing area, compression and adhesion were improved using thick fabric spats. Muscle mass, including that of the paraspinal muscles, was maintained during follow-up evaluations using computed tomography, dual-energy X-ray absorptiometry, and bioelectrical impedance analysis. The phantom limb pain in the right leg diminished with medication and prosthetic training. Her quality-of-life scores measured using the 36-item Short Form Questionnaire and the Prosthesis Evaluation Questionnaire also showed improvement. She was discharged home 5 months post-amputation. DISCUSSION: This case highlights the importance of high motivation, multidisciplinary collaboration, preservation of the trunk muscle reserve from pre-illness exercise habits, and early trunk rehabilitation to achieve successful gait acquisition with a customized transfemoral prosthesis.

  82. Establishment of a novel amyotrophic lateral sclerosis patient (TARDBP N345K/+)-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction. International-journal

    Kinya Matsuo, Jun Nagamatsu, Kazuhiro Nagata, Ryusei Umeda, Takaya Shiota, Satoru Morimoto, Naoki Suzuki, Masashi Aoki, Hideyuki Okano, Masayuki Nakamori, Hideaki Nishihara

    Frontiers in cell and developmental biology　12　1357204-1357204　2024

    DOI： 10.3389/fcell.2024.1357204 　

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    Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as a gatekeeper to protect the central nervous system (CNS) from harmful molecules in the blood and aberrant immune cell infiltration. The accumulation of evidence indicating that alterations in the peripheral milieu can contribute to neurodegeneration within the CNS suggests that the BBB may be a previously overlooked factor in the pathogenesis of ALS. Animal models suggest BBB breakdown may precede neurodegeneration and link BBB alteration to the disease progression or even onset. However, the lack of a useful patient-derived model hampers understanding the pathomechanisms of BBB dysfunction and the development of BBB-targeted therapies. In this study, we differentiated BMEC-like cells from human induced pluripotent stem cells (hiPSCs) derived from ALS patients to investigate BMEC functions in ALS patients. TARDBP N345K/+ carrying patient-derived BMEC-like cells exhibited increased permeability to small molecules due to loss of tight junction in the absence of neurodegeneration or neuroinflammation, highlighting that BMEC abnormalities in ALS are not merely secondary consequences of disease progression. Furthermore, they exhibited increased expression of cell surface adhesion molecules like ICAM-1 and VCAM-1, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types of TARDBP gene mutations (TARDBP K263E/K263E and TARDBP G295S/G295S) introduced by genome editing technology did not show such BMEC dysfunction compared to the isogenic control. Interestingly, transactive response DNA-binding protein 43 (TDP-43) was mislocalized to cytoplasm in TARDBP N345K/+ carrying model. Wnt/β-catenin signaling was downregulated in the ALS patient (TARDBP N345K/+)-derived BMEC-like cells and its activation rescued the leaky barrier phenotype and settled down VCAM-1 expressions. These results indicate that TARDBP N345K/+ carrying model recapitulated BMEC abnormalities reported in brain samples of ALS patients. This novel patient-derived BMEC-like cell is useful for the further analysis of the involvement of vascular barrier dysfunctions in the pathogenesis of ALS and for promoting therapeutic drug discovery targeting BMEC.

  83. Sporadic inclusion body myositis-derived myotube culture revealed muscle cell-autonomous expression profiles. International-journal

    Naoki Suzuki, Makoto Kanzaki, Masashi Koide, Rumiko Izumi, Ryo Fujita, Tadahisa Takahashi, Kazumi Ogawa, Yutaka Yabe, Masahiro Tsuchiya, Masako Suzuki, Ryuhei Harada, Akiyuki Ohno, Hiroya Ono, Naoko Nakamura, Kensuke Ikeda, Hitoshi Warita, Shion Osana, Yoshitsugu Oikawa, Takafumi Toyohara, Takaaki Abe, Muliang Rui, Satoru Ebihara, Ryoichi Nagatomi, Yoshihiro Hagiwara, Masashi Aoki

    PloS one　19　(8)　e0306021　2024

    DOI： 10.1371/journal.pone.0306021 　

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    Sporadic inclusion body myositis (sIBM) is a muscle disease in older people and is characterized by inflammatory cell invasion into intact muscle fibers and rimmed vacuoles. The pathomechanism of sIBM is not fully elucidated yet, and controversy exists as to whether sIBM is a primary autoimmune disease or a degenerative muscle disease with secondary inflammation. Previously, we established a method of collecting CD56-positive myoblasts from human skeletal muscle biopsy samples. We hypothesized that the myoblasts derived from these patients are useful to see the cell-autonomous pathomechanism of sIBM. With these resources, myoblasts were differentiated into myotubes, and the expression profiles of cell-autonomous pathology of sIBM were analyzed. Myoblasts from three sIBM cases and six controls were differentiated into myotubes. In the RNA-sequencing analysis of these "myotube" samples, 104 differentially expressed genes (DEGs) were found to be significantly upregulated by more than twofold in sIBM, and 13 DEGs were downregulated by less than twofold. For muscle biopsy samples, a comparative analysis was conducted to determine the extent to which "biopsy" and "myotube" samples differed. Fifty-three DEGs were extracted of which 32 (60%) had opposite directions of expression change (e.g., increased in biopsy vs decreased in myotube). Apolipoprotein E (apoE) and transmembrane protein 8C (TMEM8C or MYMK) were commonly upregulated in muscle biopsies and myotubes from sIBM. ApoE and myogenin protein levels were upregulated in sIBM. Given that enrichment analysis also captured changes in muscle contraction and development, the triggering of muscle atrophy signaling and abnormal muscle differentiation via MYMK or myogenin may be involved in the pathogenesis of sIBM. The presence of DEGs in sIBM suggests that the myotubes formed from sIBM-derived myoblasts revealed the existence of muscle cell-autonomous degeneration in sIBM. The catalog of DEGs will be an important resource for future studies on the pathogenesis of sIBM focusing on primary muscle degeneration.

  84. Zinc finger domains bind low-complexity domain polymers

    Naohiko Iguchi, Noriyoshi Isozumi, Yoshikazu Hattori, Tomohiro Imamura, Masatomo So, Hitoki Nanaura, Takao Kiriyama, Nobuyuki Eura, Minako Yamaoka, Mari Nakanishi, Masashi Mori, Shinya Ohki, Hiroyuki Kumeta, Hironori Koga, Mai Watabe, Takuya Mabuchi, Shingo Kanemura, Masaki Okumura, Takuya Yoshizawa, Ichiro Ota, Naoki Suzuki, Masashi Aoki, Yoshito Yamashiro, Tomohide Saio, Kazuma Sugie, Eiichiro Mori

    2023/10/29

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2023.10.29.564599 　

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    Self-association of low-complexity protein sequences (LC domains) is important for polymer formation. Several molecular chaperones are involved in the regulation of LC domain polymer formation. However, the mechanisms underlying cell recognition of LC domain polymers remain unclear. Here we show that zinc finger domains (ZnFs) bind LC domains of RNA-binding proteins in a cross-β polymer-dependent manner. ZnFs bound to LC domain hydrogels and suppressed LC domain polymer formation. Moreover, ZnFs preferentially recognize LC domains in the polymeric state. These findings suggest that ZnFs act as physiological regulators of LC domain polymer formation.

  85. [Efficacy of Aceneuramic Acid for Distal Myopathy with Rimmed Vacuoles].

    Masashi Aoki, Rumiko Izumi, Naoki Suzuki

    Brain and nerve = Shinkei kenkyu no shinpo　75　(10)　1149-1154　2023/10

    DOI： 10.11477/mf.1416202492 　

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    Distal myopathy with rimmed vacuoles (DMRV), also known as GNE myopathy, is a rare disease affecting the distal muscles, such as the tibialis anterior muscle. The GNE gene, which codes for a key enzyme in the sialic acid biosynthesis pathway, is mutated in a homozygous or compound heterozygous manner, and the lack of sialic acid in skeletal muscle is the critical underlying mechanism in DMRV pathogenesis. DMRV mouse models were established, and supplementation with sialic acid improved the phenotypes of the models. A phase 1 clinical trial using aceneuramic acid was conducted at Tohoku University Hospital, Japan, followed by trials using a slow-release product. A phase II/III study, subsequent extended trial, and confirmatory trial were also conducted. Regulatory approval is currently under review.

  86. GNEミオパチーに対する経口アセノイラミン酸による治療開発

    鈴木 直輝, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 井泉 瑠美子, 割田 仁, 浅田 隆太, 西野 一三, 青木 正志

    日本筋学会学術集会・筋ジストロフィー医療研究会合同学術集会プログラム・抄録集　9回・10回　63-63　2023/08

    Publisher: 日本筋学会・筋ジストロフィー医療研究会

    ISSN： 2433-975X

  87. The aminopeptidase LAP3 suppression accelerates myogenic differentiation via the AKT-TFE3 pathway in C2C12 myoblasts. International-journal

    Shion Osana, Yasuo Kitajima, Suzuki Naoki, Kazutaka Murayama, Hiroaki Takada, Ayaka Tabuchi, Yutaka Kano, Ryoichi Nagatomi

    Journal of cellular physiology　238　(9)　2103-2119　2023/07/12

    DOI： 10.1002/jcp.31070 　

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    Skeletal muscle maintenance depends largely on muscle stem cells (satellite cells) that supply myoblasts required for muscle regeneration and growth. The ubiquitin-proteasome system is the major intracellular protein degradation pathway. We previously reported that proteasome dysfunction in skeletal muscle significantly impairs muscle growth and development. Furthermore, the inhibition of aminopeptidase, a proteolytic enzyme that removes amino acids from the termini of peptides derived from proteasomal proteolysis, impairs the proliferation and differentiation ability of C2C12 myoblasts. However, no evidence has been reported on the role of aminopeptidases with different substrate specificities on myogenesis. In this study, therefore, we investigated whether the knockdown of aminopeptidases in differentiating C2C12 myoblasts affects myogenesis. The knockdown of the X-prolyl aminopeptidase 1, aspartyl aminopeptidase, leucyl-cystinyl aminopeptidase, methionyl aminopeptidase 1, methionyl aminopeptidase 2, puromycine-sensitive aminopeptidase, and arginyl aminopeptidase like 1 gene in C2C12 myoblasts resulted in defective myogenic differentiation. Surprisingly, the knockdown of leucine aminopeptidase 3 (LAP3) in C2C12 myoblasts promoted myogenic differentiation. We also found that suppression of LAP3 expression in C2C12 myoblasts resulted in the inhibition of proteasomal proteolysis, decreased intracellular branched-chain amino acid levels, and enhanced mTORC2-mediated AKT phosphorylation (S473). Furthermore, phosphorylated AKT induced the translocation of TFE3 from the nucleus to the cytoplasm, promoting myogenic differentiation through increased expression of myogenin. Overall, our study highlights the association of aminopeptidases with myogenic differentiation.

  88. A Case of Amyotrophic Lateral Sclerosis with a Priority Request for a Postmortem Kidney Donation to a Relative.

    Masaya Toyoshima, Naoki Suzuki, Shio Mitsuzawa, Temma Soga, Rumiko Izumi, Kazuhiro Mitsui, Shigehito Miyagi, Masashi Aoki, Masaaki Kato

    Internal medicine (Tokyo, Japan)　2023/05/24

    DOI： 10.2169/internalmedicine.1574-23 　

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    The patient was 57 years old when he was diagnosed with amyotrophic lateral sclerosis (ALS) at 1 year after developing bulbar symptoms. At 58 years old, he stated that he was considering donating his kidney to his son suffering from diabetic nephropathy. We confirmed the patient's intentions through repeated interviews before his death at 61 years old. Nephrectomy was performed 30 min after his cardiac death. Organ donation spontaneously proposed by an ALS patient should be considered in order to meet the requests of patients who want their families and other patients to live longer, thereby imparting a beneficial legacy through their deaths.

  89. 【骨格筋のすべて-メカニズムからサルコペニアまで】筋症状を伴う疾患 筋萎縮性側索硬化症-骨格筋の症状と分子病態

    鈴木 直輝, 割田 仁, 青木 正志

    Clinical Neuroscience　41　(2)　256-259　2023/02

    Publisher: (株)中外医学社

    ISSN： 0289-0585

  90. Videofluoroscopic Dysphagia Scale as an Additional Indicator of Gastrostomy in Patients with Amyotrophic Lateral Sclerosis with Dysphagia.

    Tomomi Shijo, Ryoukichi Ikeda, Naoki Suzuki, Jun Ohta, Jun Suzuki, Ai Hirano-Kawamoto, Kengo Kato, Kensuke Ikeda, Rumiko Izumi, Shio Mitsuzawa, Hitoshi Warita, Masaaki Kato, Masashi Aoki, Yukio Katori

    The Tohoku journal of experimental medicine　259　(4)　293-300　2023/01/26

    DOI： 10.1620/tjem.2023.J005 　

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    Pseudobulbar palsy and bulbar palsy cause dysphagia in patients with amyotrophic lateral sclerosis (ALS). Dysphagia in patients with ALS not only increases the risk of aspiration and pneumonia but also leads to malnutrition and weight loss, which are poor prognostic factors. Gastrostomy is the preferred route of feeding and nutritional support in patients with dysphagia. However, there are no established standards to determine the ideal timing of gastrostomy for patients with ALS. Therefore, we used the videofluoroscopic dysphagia scale (VDS), which objectively quantifies swallowing function, in videofluoroscopic swallowing study (VFSS) to investigate whether this scale at diagnosis can be a useful predictor for the timing of gastrostomy. We retrospectively evaluated 22 patients with ALS who were diagnosed at our hospital. We assessed the VDS scores in all patients within 3 months of diagnosis. A decline in the ALS functional rating scale revised (ALSFRS-R) scores was used as an indicator of disease progression. As a result, we found that the VDS score of the pharyngeal phase and the total VDS score were significantly correlated with the ΔALSFRS-R scores. These scores were also associated with the existing indicators for the timing of gastrostomy, i.e., decreased body weight and percent-predicted forced vital capacity. We demonstrated the noninferiority of the VDS scores relative to the existing indicators. In addition, the VDS score of the pharyngeal phase was significantly correlated with the time from diagnosis to gastrostomy. The VDS score could estimate the timing of gastrostomy in patients with ALS with dysphagia at diagnosis.

  91. 東北大学病院難病医療連携センターについて

    関本 聖子, 遠藤 久美子, 遠藤 恵, 石橋 渚子, 山内 悦子, 松本 有史, 鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    日本難病医療ネットワーク学会機関誌　10　(1)　106-106　2022/11

    Publisher: 日本難病医療ネットワーク学会

    ISSN： 2188-1006

  92. 病的バリアントと確定しがたいdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 戸恒 智子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 吉岡 勝, 馬場 徹, 大泉 英樹, 田中 洋康, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　62　(Suppl.)　S221-S221　2022/10

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  93. ALS発症から診断までの期間は疾患進行の予測因子となりうる

    池田 謙輔, 四條 友望, 鈴木 直輝, 割田 仁, 川内 裕子, 光澤 志緒, 井泉 瑠美子, 黒田 宙, 加藤 昌昭, 青木 正志

    臨床神経学　62　(Suppl.)　S328-S328　2022/10

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  94. 筋萎縮性側索硬化症では片側のみで正中神経刺激巨大体性感覚誘発電位を認めることがある

    板橋 泉, 浅黄 優, 四條 友望, 鈴木 直輝, 坂本 美佳, 佐藤 貴文, 小澤 鹿子, 青木 正志, 三木 俊, 中里 信和

    臨床神経生理学　50　(5)　400-400　2022/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN： 1345-7101

    eISSN： 2188-031X

  95. 【炎症性筋疾患に関する最新の知見】封入体筋炎

    井泉 瑠美子, 鈴木 直輝, 青木 正志

    臨床免疫・アレルギー科　78　(4)　430-437　2022/10

    Publisher: (有)科学評論社

    ISSN： 1881-1930

  96. 大規模レジストリデータベース(PRO-ACT)を活用したALSに対するロピニロール塩酸塩の有効性の検証

    森本 悟, 高橋 愼一, 伊東 大介, 伊達 悠岳, 岡田 健佑, Chai Muh Chy, 西山 亜由美, 鈴木 直輝, 平井 美和, 加部 泰明, 末松 誠, 陣崎 雅弘, 青木 正志, 佐藤 泰憲, 中原 仁, 鈴木 則宏, 岡野 栄之

    神経治療学　39　(6)　S257-S257　2022/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  97. Little involvement of recycled-amino acids from proteasomal proteolysis in de novo protein synthesis

    Shion Osana, Yasuo Kitajima, Suzuki Naoki, Hiroaki Takada, Kazutaka Murayama, Yutaka Kano, Ryoichi Nagatomi

    Biochemical and Biophysical Research Communications　2022/10

    Publisher: Elsevier BV

    DOI： 10.1016/j.bbrc.2022.09.113 　

    ISSN： 0006-291X

  98. A case of giant dental calculus in a patient with centronuclear myopathy

    Ryosuke Iwama, Hirokazu Nagai, Naoki Suzuki, Rumiko Izumi, Hiroyuki Kumamoto, Tetsu Takahashi

    Special Care in Dentistry　2022/08/28

    Publisher: Wiley

    DOI： 10.1111/scd.12772 　

    ISSN： 0275-1879

    eISSN： 1754-4505

  99. Patulous Eustachian Tube Patients With Oculopharyngeal Muscular Dystrophy. International-journal

    Kento Ishigakii, Ryoukichi Ikeda, Jun Suzuki, Ai Hirano-Kawamoto, Jun Ohta, Kengo Kato, Rumiko Izumi, Naoki Suzuki, Masashi Aoki, Tetsuaki Kawase, Yukio Katori

    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology　43　(4)　e442-e445　2022/04/01

    DOI： 10.1097/MAO.0000000000003494 　

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    OBJECTIVES: To describe cases of patulous Eustachian tube (PET) or patent ET conditions in oculopharyngeal muscular dystrophy (OPMD). PATIENTS: Four cases of PET or patent ET conditions with OPMD. MAIN OUTCOME MEASURES: Clinical case records, objective ET function tests (tubo-tympano-aerodynamic graphy and sonotubometry), and swallowing function (videoendoscopic examination and Food Intake Level Scale) were analyzed. RESULTS: Two cases of definite PET, one case of possible PET, and one case lacking aural symptoms with findings of patent ET. All patients have ptosis, and three cases have dysphagia. Body mass index indicated that three cases were underweight. Magnetic resonance imaging in case 4 showed atrophy and fat replacement of palatine and masticatory muscles. CONCLUSIONS: It is important to consider PET or patent ET conditions when OPMD patients describe aural symptoms.

  100. Anti-NXP2 antibody-positive dermatomyositis developed after COVID-19 manifesting as type I interferonopathy. International-journal

    Yuri Okada, Rumiko Izumi, Tatsuhiko Hosaka, Satoshi Watanabe, Tomomi Shijo, Naokazu Hatchome, Risa Konishi, Yuki Ichimura, Naoko Okiyama, Naoki Suzuki, Tatsuro Misu, Masashi Aoki

    Rheumatology (Oxford, England)　61　(4)　e90-e92　2021/11/30

    DOI： 10.1093/rheumatology/keab872 　

  101. ALSに対するロピニロール塩酸塩に関するランダム化臨床試験の結果(ROPALS)(Results Of A Randomized Clinical Trial of Ropinirole Hydrochloride For ALS(ROPALS))

    高橋 愼一, 森本 悟, 伊東 大介, 伊達 悠岳, 岡田 健佑, Chai Muh Chyi, 西山 亜由美, 鈴木 直輝, 平井 美和, 加部 泰明, 末松 誠, 陣崎 雅弘, 青木 正志, 佐藤 泰憲, 中原 仁, 鈴木 則宏, 岡野 栄之

    脳循環代謝　33　(1)　129-129　2021/11

    Publisher: (一社)日本脳循環代謝学会

    ISSN： 0915-9401

    eISSN： 2188-7519

  102. iPS細胞創薬に基づいた筋萎縮性側索硬化症(ALS)に対するロピニロール塩酸塩の医師主導治験(ROPALS試験)

    森本 悟, 高橋 愼一, 伊東 大介, 伊達 悠岳, 岡田 健佑, Chai Muh Chyi, 西山 亜由美, 鈴木 直輝, 平井 美和, 加部 泰明, 末松 誠, 陣崎 雅弘, 青木 正志, 佐藤 泰憲, 中原 仁, 鈴木 則宏, 岡野 栄之

    神経治療学　38　(6)　S261-S261　2021/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  103. A rare case of sporadic inclusion body myositis and rheumatoid arthritis exhibiting ectopic lymphoid follicle-like structures: a case report and literature review. International-journal

    Kazutoshi Konomatsu, Rumiko Izumi, Naoki Suzuki, Yoshiki Takai, Yuko Shirota, Ryoko Saito, Hiroshi Kuroda, Masashi Aoki

    Neuromuscular disorders : NMD　31　(9)　870-876　2021/07/08

    DOI： 10.1016/j.nmd.2021.07.002 　

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    Sporadic inclusion body myositis (sIBM) is a degenerative, intractable, inflammatory myopathy with an immune pathomechanism. We report on a case of a 44-year-old Japanese man who began developing progressive muscle weakness at age 40. Rheumatoid arthritis symptoms manifested at 43 with strongly positive anti-cyclic citrullinated peptide antibodies. Along with typical sIBM pathology, a muscle biopsy revealed dramatic inflammation with prominent perivascular B-cell infiltration forming ectopic lymphoid follicle-like structures (ELFLSs). Exome sequencing identified no causative variants of hereditary myopathy or immune disorders. A combination of immunotherapy slowed the progression of the muscular symptoms. This unusual form of sIBM, including earlier age at onset, a partial response to immunotherapy, and a histopathology presenting B-cell infiltrate with ectopic lymphoid follicle-like structures, indicates a possible association of rheumatoid arthritis and heterogeneity with the autoimmune involvement of sIBM. We review the clinical and pathological features of patients with rheumatoid arthritis associated sIBM in the literature.

  104. 両側小脳病変を呈し、MELASが疑われた兄妹例

    船山 由希乃, 原田 龍平, 鈴木 直輝, 三須 建郎, 青木 正志

    臨床神経学　61　(7)　509-509　2021/07

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  105. Puromycin-sensitive aminopeptidase is required for C2C12 myoblast proliferation and differentiation. International-journal

    Shion Osana, Yasuo Kitajima, Naoki Suzuki, Aki Nunomiya, Hiroaki Takada, Takahiro Kubota, Kazutaka Murayama, Ryoichi Nagatomi

    Journal of cellular physiology　236　(7)　5293-5305　2021/07

    DOI： 10.1002/jcp.30237 　

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    The ubiquitin-proteasome system is a major protein degradation pathway in the cell. Proteasomes produce several peptides that are rapidly degraded to free amino acids by intracellular aminopeptidases. Our previous studies reported that proteolysis via proteasomes and aminopeptidases is required for myoblast proliferation and differentiation. However, the role of intracellular aminopeptidases in myoblast proliferation and differentiation had not been clarified. In this study, we investigated the effects of puromycin-sensitive aminopeptidase (PSA) on C2C12 myoblast proliferation and differentiation by knocking down PSA. Aminopeptidase enzymatic activity was reduced in PSA-knockdown myoblasts. Knockdown of PSA induced impaired cell cycle progression in C2C12 myoblasts and accumulation of cells at the G2/M phase. Additionally, after the induction of myogenic differentiation in PSA-knockdown myoblasts, multinucleated circular-shaped myotubes with impaired cell polarity were frequently identified. Cell division cycle 42 (CDC42) knockdown in myoblasts resulted in a loss of cell polarity and the formation of multinucleated circular-shaped myotubes, which were similar to PSA-knockdown myoblasts. These data suggest that PSA is required for the proliferation of myoblasts in the growth phase and for the determination of cell polarity and elongation of myotubes in the differentiation phase.

  106. A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy. International-journal

    Aya Inoue-Shibui, Tetsuya Niihori, Michio Kobayashi, Naoki Suzuki, Rumiko Izumi, Hitoshi Warita, Kenju Hara, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Ichizo Nishino, Masashi Aoki, Yoko Aoki

    Journal of human genetics　66　(10)　965-972　2021/03/20

    DOI： 10.1038/s10038-021-00916-y 　

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    Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.

  107. 日本人一般集団に高頻度で見出されるジスフェルリン遺伝子のc.3725G>A(p.R1242H)バリアントの臨床像の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 戸恒 智子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究　7　65-65　2021/01

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  108. siRNA knockdown of alanine aminopeptidase impairs myoblast proliferation and differentiation. International-journal

    Shion Osana, Yasuo Kitajima, Naoki Suzuki, Yidan Xu, Kazutaka Murayama, Ryoichi Nagatomi

    Experimental cell research　397　(1)　112337-112337　2020/12/01

    DOI： 10.1016/j.yexcr.2020.112337 　

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    A large number of intracellular proteins are degraded by the ubiquitin-proteasome system, one of the major protein degradation pathways. It produces peptides of several different sizes through protein degradation, and these peptides are rapidly degraded into free amino acids by various intracellular aminopeptidases. Previously, we reported that the activity of proteasomes and aminopeptidases in the proteolysis pathway are necessary for myoblast proliferation and differentiation. However, the detailed function of intracellular aminopeptidases in myoblast proliferation and differentiation has not yet been elucidated. In this study, we focused on alanine aminopeptidase (APN) and investigated the function of APN in C2C12 myoblast proliferation and differentiation. In myoblasts and myotubes, APN was mainly localized in the cell membrane as well as expressed at low levels in the cytoplasm and nucleus. The reduction of the APN enzymatic activity impaired the cell cycle progression in C2C12 myoblasts. In addition, apoptosis was induced after APN-knockdown. Finally, myogenic differentiation was also delayed in the APN-suppressed myoblasts. These findings indicate that APN is required for myoblast proliferation and differentiation.

  109. 当院におけるALS患者に対する誤嚥防止術5例の長期経過

    曽我 天馬, 井泉 瑠美子, 鈴木 直輝, 川内 裕子, 加藤 健吾, 香取 幸夫, 青木 正志, 加藤 昌昭

    臨床神経学　60　(Suppl.)　S450-S450　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  110. 知っておきたい!進化する難治性筋疾患の新展開 封入体筋炎の診断と新たな治療に向けて

    青木 正志, 鈴木 直輝, 井泉 瑠美子, 割田 仁, 森 まどか, 山下 賢, 橋口 昭大, 梶 龍兒, 村田 顕也, 杉江 和馬, 西野 一三

    臨床神経学　60　(Suppl.)　S90-S90　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  111. 日本人一般集団に高頻度で見出されるdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　60　(Suppl.)　S387-S387　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  112. ジスフェルリン異常症209家系の臨床遺伝学的特徴

    井泉 瑠美子, 高橋 俊明, 鈴木 直輝, 新堀 哲也, 小野 洋也, 中村 尚子, 堅田 慎一, 加藤 昌昭, 割田 仁, 竪山 真規, 青木 洋子, 青木 正志

    臨床神経学　60　(Suppl.)　S387-S387　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  113. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学　37　(6)　S101-S101　2020/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  114. The ubiquitin-proteasome system in regulation of the skeletal muscle homeostasis and atrophy: from basic science to disorders. Peer-reviewed

    Yasuo Kitajima, Kiyoshi Yoshioka, Naoki Suzuki

    The journal of physiological sciences : JPS　70　(1)　40-40　2020/09/16

    DOI： 10.1186/s12576-020-00768-9 　

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    Skeletal muscle is one of the most abundant and highly plastic tissues. The ubiquitin-proteasome system (UPS) is recognised as a major intracellular protein degradation system, and its function is important for muscle homeostasis and health. Although UPS plays an essential role in protein degradation during muscle atrophy, leading to the loss of muscle mass and strength, its deficit negatively impacts muscle homeostasis and leads to the occurrence of several pathological phenotypes. A growing number of studies have linked UPS impairment not only to matured muscle fibre degeneration and weakness, but also to muscle stem cells and deficiency in regeneration. Emerging evidence suggests possible links between abnormal UPS regulation and several types of muscle diseases. Therefore, understanding of the role of UPS in skeletal muscle may provide novel therapeutic insights to counteract muscle wasting, and various muscle diseases. In this review, we focussed on the role of proteasomes in skeletal muscle and its regeneration, including a brief explanation of the structure of proteasomes. In addition, we summarised the recent findings on several diseases and elaborated on how the UPS is related to their pathological states.

  115. 【神経疾患治療の進歩2019】運動ニューロン疾患の治療の進歩

    秋山 徹也, 割田 仁, 鈴木 直輝, 青木 正志

    神経治療学　37　(5)　736-740　2020/09

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  116. 【神経疾患治療の進歩2019】運動ニューロン疾患の治療の進歩

    秋山 徹也, 割田 仁, 鈴木 直輝, 青木 正志

    神経治療学　37　(5)　736-740　2020/09

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  117. A case of inflammatory myopathy with anti-PM/Scl antibodies myopathologically presenting as polymyositis with mitochondrial pathology

    Arifumi Matsumoto, Rumiko Izumi, Naoto Sugeno, Naoki Suzuki, Chihiro Namatame, Temma Soga, Ayumi Nishiyama, Hiroshi Kuroda, Masashi Aoki, Isao Nagano

    NEUROLOGY AND CLINICAL NEUROSCIENCE　8　(5)　335-339　2020/09

    DOI： 10.1111/ncn3.12429 　

    ISSN： 2049-4173

  118. Generation of an ALS human iPSC line KEIOi001-A from peripheral blood of a Charcot disease-affected patient carrying TARDBP p.N345K heterozygous SNP mutation. International-journal Peer-reviewed

    Nicolas Leventoux, Satoru Morimoto, Kenju Hara, Shiho Nakamura, Fumiko Ozawa, Shio Mitsuzawa, Tetsuya Akiyama, Ayumi Nishiyama, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Hideyuki Okano

    Stem cell research　47　101896-101896　2020/06/28

    DOI： 10.1016/j.scr.2020.101896 　

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    Amyotrophic Lateral Sclerosis is the most common motor neuron degenerative disease in adults, and TARDBP gene mutations have been reported to be involved in the pathogenesis. We present here how we generated the human induced pluripotent stem cell (hiPSC) line KEIOi001-A/SM4-4-5 from the peripheral blood of a 63-year-old male patient presenting the c.1035C > G heterozygous SNP mutation in the TARDBP gene locus. The established hiPSC line does not express the exogenous reprogramming factors oriP nor EBNA1 and shows no karyotypic abnormalities, while it expresses pluripotent stem cell markers, presents the SNP mutation and is capable of three-germ layers differentiation in vitro.

  119. 【筋炎の診断と治療の新たな展開】増えてきた封入体筋炎

    鈴木 直輝, 井泉 瑠美子, 青木 正志

    神経治療学　37　(2)　135-140　2020/03

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  120. Neutral Lipid Storage Disease Associated with the PNPLA2 Gene: Case Report and Literature Review. International-journal Peer-reviewed

    Makoto Samukawa, Naoko Nakamura, Makito Hirano, Miyuki Morikawa, Hanami Sakata, Ichizo Nishino, Rumiko Izumi, Naoki Suzuki, Hiroshi Kuroda, Kensuke Shiga, Kazumasa Saigoh, Masashi Aoki, Susumu Kusunoki

    European neurology　83　(3)　317-322　2020

    DOI： 10.1159/000508346 　

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    Mutations in the PNPLA2 gene cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy. We report a detailed case study of a 53-year-old man with NLSDM. The PNPLA2 gene was analyzed according to the reported method. We summarized the clinical, laboratory, and genetic information of 56 patients, including our patient and 55 other reported patients with homozygous or compound heterozygous mutations in the PNPLA2 gene. We found a novel homozygous mutation (c.194delC) in the PNPLA2 gene that resulted in frameshift. The patient suffered from normal-tension glaucoma and pulmonary cysts, symptoms that are relatively common in the elderly but were not previously reported for this disease. Our summary confirmed that Jordan's anomaly, polymorphonuclear leukocytes with lipid accumulation, was the most consistent finding of this disease. Because this disease is potentially treatable, our results may help rapid and correct diagnosis.

  121. 封入体筋炎患者を対象とするBYM338の後期第II相/第III相試験(RESILIENT) 日本人部分集団データ Peer-reviewed

    森 まどか, 山下 賢, 鈴木 直輝, 勝野 雅央, 村田 顕也, 野寺 裕之, 手島 梨恵, 稲村 達海, 西野 一三, 青木 正志

    臨床神経学　59　(12)　806-813　2019/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  122. [Late phase II/III study of BYM338 in patients with sporadic inclusion body myositis (RESILIENT): Japanese cohort data]. Peer-reviewed

    Madoka Mori-Yoshimura, Satoshi Yamashita, Naoki Suzuki, Masahisa Katsuno, Kenya Murata, Hiroyuki Nodera, Rie Teshima, Tatsumi Inamura, Ichizo Nishino, Masashi Aoki

    Rinsho shinkeigaku = Clinical neurology　59　(12)　806-813　2019/12

    Publisher:

    DOI： 10.5692/clinicalneurol.cn-001325 　

    ISSN： 0009-918X

    eISSN： 1882-0654

  123. 侵襲的人工呼吸器装着ALS患者の定期的評価入院における身体機能評価表の作成および運用の試み

    石橋 渚子, 関本 聖子, 遠藤 久美子, 山内 悦子, 川内 裕子, 松本 有史, 鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    日本難病医療ネットワーク学会機関誌　7　(1)　84-84　2019/11

    Publisher: 日本難病医療ネットワーク学会

    ISSN： 2188-1006

  124. 頭部外傷を契機に発症した抗MOG抗体関連脳脊髄炎の一例

    佐藤 一輝, 西山 亜由美, 鈴木 直輝, 張替 宗介, 齋藤 早紀, 池田 謙輔, 西山 修平, 三須 建郎, 割田 仁, 黒田 宙, 青木 正志

    臨床神経学　59　(11)　760-760　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  125. 日本人dysferlin遺伝子解析で見出されたバリアントの一般頻度による病的意義の推定

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　59　(Suppl.)　S257-S257　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  126. [Familial Amyotrophic Lateral Sclerosis]. Peer-reviewed

    Naoki Suzuki, Ayumi Nishiyama, Masaaki Kato, Hitoshi Warita, Masashi Aoki

    Brain and nerve = Shinkei kenkyu no shinpo　71　(11)　1169-1181　2019/11

    DOI： 10.11477/mf.1416201427 　

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    Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. Riluzole and edaravone are the only approved drugs available in Japan to date. Approximately 10% of ALS cases are familial in rature, defined as the existence of disease-causing mutation. SOD1 is the most frequent causative gene for ALS among Japanese individuals, while C9orf72 mutation is more prevalent in Western countries. Genotype-phenotype correlation described in the literature of familial ALS enables to establish models of the disease. This review article describes the clinical characteristics of familial ALS based on each disease-causing mutation. The pathomechanism of ALS including proteostasis, RNA metabolism, and axonal pathology are discussed in detail. We also reviewed the status of development of therapeutic strategies for familial ALS based on analysis of animal models and induced pluripotent stem cells.

  127. [Application of Hepatocyte Growth Factor for Amyotrophic Lateral Sclerosis]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Masaaki Kato, Naoki Suzuki

    Brain and nerve = Shinkei kenkyu no shinpo　71　(11)　1253-1260　2019/11

    DOI： 10.11477/mf.1416201435 　

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    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. About 10% of all ALS cases are familial, and we have identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan (Nishiyama A, 2017). From studies of the TDP43, FUS, and C9orf72 genes, perturbations of RNA processing can be highly adverse in motor neurons. Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to transgenic rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease by 63% (Ishigaki A, 2007). To translate this strategy to human treatment, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. We conducted a first-in-human phase I trial of intrathecal hrHGF in 15 Japanese patients with ALS (Warita H, 2019). Based on the results, we are conducting a phase II trial of intrathecal hrHGF for patients with ALS.

  128. 遺伝性筋疾患におけるトランスレーショナル・リサーチ GNEミオパチーの治療法開発 Peer-reviewed

    青木 正志, 鈴木 直輝, 割田 仁, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 西野 一三

    神経治療学　36　(6)　S163-S163　2019/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  129. FDG-PET detects extensive calcinosis cutis in anti-NXP2 antibody-positive dermatomyositis. International-journal Peer-reviewed

    Naoko Nakamura, Rumiko Izumi, Yosuke Hoshi, Yoshiki Takai, Risako Ono, Naoki Suzuki, Taichi Nagai, Yusho Ishii, Tomonori Ishii, Hideo Harigae, Shuko Okada, Setsuya Aiba, Naoko Okiyama, Manabu Fujimoto, Hiroshi Kuroda, Maki Tateyama, Masashi Aoki

    Rheumatology (Oxford, England)　58　(10)　1888-1888　2019/10/01

    DOI： 10.1093/rheumatology/kez083 　

    ISSN： 1462-0324

  130. Review/Advances in Neurological Therapeutics (2018). Motor neuron disease Peer-reviewed

    Akiyama Tetsuya, Suzuki Naoki, Warita Hitoshi, Aoki Masashi

    Neurological Therapeutics　36　(5)　584-587　2019/09

    Publisher: Japanese Society of Neurological Therapeutics

    DOI： 10.15082/jsnt.36.5_584 　

    ISSN： 0916-8443

    eISSN： 2189-7824

  131. 日本人dysferlin遺伝子解析で見出されたバリアントのデータベースによる検討 Peer-reviewed

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    日本筋学会学術集会プログラム・抄録集　5回　172-172　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  132. 封入体筋炎の患者アンケート調査 Peer-reviewed

    鈴木 直輝, 森 まどか, 山下 賢, 木村 円, 竪山 真規, 井泉 瑠美子, 小野 洋也, 高橋 俊明, 西野 一三, 青木 正志

    日本筋学会学術集会プログラム・抄録集　5回　191-191　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  133. p.N345K mutation in TARDBP in a patient with familial amyotrophic lateral sclerosis: An autopsy case. International-journal Peer-reviewed

    Takahiro Takeda, Mutsumi Iijima, Yuko Shimizu, Hiroshi Yoshizawa, Mayu Miyashiro, Hiromi Onizuka, Tomoko Yamamoto, Ayumi Nishiyama, Naoki Suzuki, Masashi Aoki, Noriyuki Shibata, Kazuo Kitagawa

    Neuropathology : official journal of the Japanese Society of Neuropathology　39　(4)　286-293　2019/08

    DOI： 10.1111/neup.12559 　

    ISSN： 0919-6544

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    We report the neuropathology of a patient with a family history of amyotrophic lateral sclerosis (ALS) and a p.N345K mutation in the transactivation response DNA-binding protein 43 kDa (TDP-43) gene (TARDBP). A 62-year-old man had bulbar palsy with progressive weakness in the extremities. Neurological examination revealed evident upper motor neuron signs and lower motor neuron involvement corroborated by needle electromyography. The patient was diagnosed as having probable ALS according to the revised El Escorial diagnostic criteria and was eventually diagnosed with familial ALS. At 65 years of age, respiratory failure became critical, and artificial ventilation was initiated. At 70 years of age, the patient died from a urinary tract infection. Histopathological investigation showed Bunina bodies in the remaining motor neurons and anterolateral funicular myelin pallor in the spinal cord. TDP-43-positive cytoplasmic inclusions were quite rare in the spinal cord motor neurons, being predominantly present in the glial cells (especially astrocytes) of the spinal cord anterior horn. Although the reason for the preferential vulnerability of spinal glial cells to TARDBP mutations remains unclear, our findings indicate that TARDBP p.N345K mutation could have an influence on the topography of TDP-43 aggregation.

  134. Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study. International-journal Peer-reviewed

    Aya Inoue-Shibui, Masaaki Kato, Naoki Suzuki, Junpei Kobayashi, Yoshiki Takai, Rumiko Izumi, Yuuko Kawauchi, Hiroshi Kuroda, Hitoshi Warita, Masashi Aoki

    BMC neurology　19　(1)　72-72　2019/04/27

    DOI： 10.1186/s12883-019-1299-1 　

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    BACKGROUND: Riluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events. METHODS: Patients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded. RESULTS: A total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment. CONCLUSION: Riluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.

  135. A juvenile sporadic amyotrophic lateral sclerosis case with P525L mutation in the FUS gene: A rare co-occurrence of autism spectrum disorder and tremor. International-journal Peer-reviewed

    Nobuyuki Eura, Kazuma Sugie, Naoki Suzuki, Takao Kiriyama, Tesseki Izumi, Naoko Shimakura, Masaaki Kato, Masashi Aoki

    Journal of the neurological sciences　398　67-68　2019/03/15

    DOI： 10.1016/j.jns.2019.01.032 　

    ISSN： 0022-510X

  136. A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. International-journal Peer-reviewed

    Takuya Miyabayashi, Tatsuhiro Ochiai, Naoki Suzuki, Masashi Aoki, Takehiko Inui, Yukimune Okubo, Ryo Sato, Noriko Togashi, Hiroshi Takashima, Hiroyuki Ishiura, Shoji Tsuji, Kishin Koh, Yoshihisa Takiyama, Kazuhiro Haginoya

    Journal of human genetics　64　(2)　171-176　2019/02

    DOI： 10.1038/s10038-018-0538-4 　

    ISSN： 1434-5161

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    The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.

  137. Extranodal NK/T-cell Lymphoma Mimicking Granulomatous Myositis. Peer-reviewed

    Norihiko Kawaguchi, Rumiko Izumi, Masahiro Kobayashi, Maki Tateyama, Naoki Suzuki, Fumiyoshi Fujishima, Juichi Fujimori, Masashi Aoki, Ichiro Nakashima

    Internal medicine (Tokyo, Japan)　58　(2)　277-282　2019/01/15

    DOI： 10.2169/internalmedicine.0859-18 　

    ISSN： 0918-2918

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    Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma that typically develops in the upper aerodigestive tract. We encountered an ENKTL patient who presented with generalized muscle weakness with eyelid swelling, diplopia, and facial edema. A muscle biopsy revealed lymphocytic infiltration without significant atypia; some lymphocytes formed granuloma-like structures. Although the initial response to steroids was encouraging, an ulcerative eruption appeared in the thigh, and a skin biopsy revealed lymphocytes with atypia. A re-analysis of the muscle biopsy with additional immunohistochemistry revealed neoplastic NK/T lymphocytes in the granulomatous structures. Our case highlights the significance of re-evaluating muscle biopsy specimens in cases of atypical myositis.

  138. Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Tomomi Shijo, Hitoshi Warita, Naoki Suzuki, Kensuke Ikeda, Shio Mitsuzawa, Tetsuya Akiyama, Hiroya Ono, Ayumi Nishiyama, Rumiko Izumi, Yasuo Kitajima, Masashi Aoki

    Experimental neurology　307　164-179　2018/09

    DOI： 10.1016/j.expneurol.2018.06.009 　

    ISSN： 0014-4886

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    Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosis in patients with ALS remain unresolved. We focused on bone morphogenetic proteins as a major soluble factor that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP4 was progressively up-regulated in reactive astrocytes of the spinal ventral horns, whereas the BMP-antagonist noggin was decreased in association with neuronal degeneration. Continuous intrathecal noggin supplementation after disease onset significantly ameliorated motor dysfunction symptoms, neurogenic muscle atrophy, and extended survival of symptomatic ALS model rats, despite lack of deterrence against neuronal death itself. The exogenous noggin inhibited astrocytic hypertrophy, astrocytogenesis, and neuroinflammation by inactivating both Smad1/5/8 and p38 mitogen-activated protein kinase pathways. Moreover, intrathecal infusion of a Bmp4-targeted antisense oligonucleotides and provided selective Bmp4 knockdown in vivo, which suppressed astrocyte and microglia activation, reproducing the aforementioned results by noggin treatment. Collectively, we clarified the involvement of BMP4 in the processes of excessive gliosis that exacerbate the disease progression of the ALS model rats. Our study demonstrated that BMP4, with its downstream signaling, might be a novel therapeutic target for disease-modifying therapies in ALS.

  139. TARDBP p.G376D mutation, found in rapid progressive familial ALS, induces mislocalization of TDP-43. International-journal Peer-reviewed

    Shio Mitsuzawa, Tetsuya Akiyama, Ayumi Nishiyama, Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Rumiko Izumi, Shion Osana, Shingo Koyama, Takeo Kato, Yoshihiro Suzuki, Masashi Aoki

    eNeurologicalSci　11　20-22　2018/06

    DOI： 10.1016/j.ensci.2018.04.001 　

  140. Five-year history of dysphagia as a sole initial symptom in inclusion body myositis. International-journal Peer-reviewed

    Saori Shibata, Rumiko Izumi, Tomonori Hara, Ryuji Ohshima, Naoko Nakamura, Naoki Suzuki, Kengo Kato, Yukio Katori, Maki Tateyama, Hiroshi Kuroda, Masashi Aoki

    Journal of the neurological sciences　381　325-327　2017/10/15

    DOI： 10.1016/j.jns.2017.09.014 　

    ISSN： 0022-510X

  141. Role of the ubiquitin-proteasome pathway in skeletal muscle Peer-reviewed

    Kitajima, Y., Suzuki, N.

    The Plasticity of Skeletal Muscle: From Molecular Mechanism to Clinical Applications　2017/03

    Publisher: The Plasticity of Skeletal Muscle: From Molecular Mechanism to Clinical Applications

    DOI： 10.1007/978-981-10-3292-9_2 　

  142. [Therapeutic development for GNE myopathy.] Peer-reviewed

    Naoki Suzuki

    Clinical Calcium　27　(3)　429-434　2017

    ISSN： 0917-5857

  143. Multicenter questionnaire survey for sporadic inclusion body myositis in Japan. International-journal Peer-reviewed

    Naoki Suzuki, Madoka Mori-Yoshimura, Satoshi Yamashita, Satoshi Nakano, Ken-Ya Murata, Yukie Inamori, Naoko Matsui, En Kimura, Hirofumi Kusaka, Tomoyoshi Kondo, Itsuro Higuchi, Ryuji Kaji, Maki Tateyama, Rumiko Izumi, Hiroya Ono, Masaaki Kato, Hitoshi Warita, Toshiaki Takahashi, Ichizo Nishino, Masashi Aoki

    Orphanet journal of rare diseases　11　(1)　146-146　2016/11/08

    DOI： 10.1186/s13023-016-0524-x 　

    eISSN： 1750-1172

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    BACKGROUND: Sporadic inclusion body myositis (sIBM) is the most prevalent acquired muscle disease in the elderly. sIBM is an intractable and progressive disease of unknown cause and without effective treatment. The etiology of sIBM is still unknown; however, genetic factors, aging, lifestyles, and environmental factors may be involved. The purpose of this study is to elucidate the cross-sectional profile of patients affected by sIBM in Japan. METHODS: We surveyed patient data for 146 cases diagnosed at a number of centers across Japan. We also issued a questionnaire for 67 patients and direct caregivers to further elucidate the natural history of the disease. RESULTS: The mean age at the onset was 63.4 ± 9.2 years. The mean length of time from the onset to diagnosis was 55.52 ± 49.72 months, suggesting that there is a difficulty in diagnosing this disease with long-term consequences because of late treatment. 73 % described the psychological/mental aspect of the disease. The most popular primary caregiver was the patient's spouse and 57 % patients mentioned that they were having problems managing the finances. CONCLUSIONS: Through these surveys, we described the cross-sectional profiles of sIBM in Japan. Many patients described psychological/mental and financial anxiety because of the aged profile of sIBM patients. The profiles of sIBM patients are similar to those in Western countries.

  144. Prominent sensory involvement in a case of familial amyotrophic lateral sclerosis carrying the L8V SOD1 mutation. International-journal Peer-reviewed

    Ayumi Nishiyama, Hitoshi Warita, Toshiaki Takahashi, Naoki Suzuki, Shuhei Nishiyama, Ohito Tano, Tetsuya Akiyama, Yasuaki Watanabe, Kenta Takahashi, Hiroshi Kuroda, Masaaki Kato, Maki Tateyama, Tetsuya Niihori, Yoko Aoki, Masashi Aoki

    Clinical neurology and neurosurgery　150　194-196　2016/11

    DOI： 10.1016/j.clineuro.2016.08.008 　

    ISSN： 0303-8467

  145. Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUS(P525L) mutation. International-journal Peer-reviewed

    Hitoshi Aizawa, Takuto Hideyama, Takenari Yamashita, Takashi Kimura, Naoki Suzuki, Masashi Aoki, Shin Kwak

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia　32　128-9　2016/10

    DOI： 10.1016/j.jocn.2015.12.039 　

    ISSN： 0967-5868

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    Mutations in the fused in sarcoma (FUS) gene can cause amyotrophic lateral sclerosis (ALS), and FUS gene mutations have been reported in sporadic ALS patients with basophilic cytoplasmic inclusions. Deficiency of adenosine deaminase acting on RNA 2 (ADAR2), an enzyme that specifically catalyzes GluA2 Q/R site-editing, has been reported in considerable proportions of spinal motor neurons of the majority of sporadic ALS patients. We describe the relationship between GluA2 Q/R site-editing efficiency and FUS-positive inclusions in a patient with FUS(P525L). A 24-year-old woman with ALS presented with basophilic cytoplasmic inclusions, significantly reduced GluA2 Q/R site-editing efficiency in the spinal motor neurons, and markedly decreased ADAR2 mRNA levels. Neuropathologic examination showed that not all spinal motor neurons expressed ADAR2 and revealed FUS-positive cytoplasmic inclusions in motor neurons irrespective of ADAR2 immunoreactivity. There were no phosphorylated transactive response (TAR) DNA-binding protein 43 kDa (TDP-43)-positive inclusions, indicating that there was no tight correlation between ADAR2 deficiency and TDP-43 deposition. ADAR2 deficiency can occur in ALS patients with a FUS(P525L) mutation and is unrelated to the presence of FUS-positive inclusions. FUS-associated ALS may share neurodegenerative characteristics with classical sporadic ALS.

  146. Genotype-phenotype relationships in familial amyotrophic lateral sclerosis with FUS/TLS mutations in Japan. International-journal Peer-reviewed

    Tetsuya Akiyama, Hitoshi Warita, Masaaki Kato, Ayumi Nishiyama, Rumiko Izumi, Chikako Ikeda, Masaki Kamada, Naoki Suzuki, Masashi Aoki

    Muscle & nerve　54　(3)　398-404　2016/09

    DOI： 10.1002/mus.25061 　

    ISSN： 0148-639X

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    INTRODUCTION: We investigated possible genotype-phenotype correlations in Japanese patients with familial amyotrophic lateral sclerosis (FALS) carrying fused in sarcoma/translated in liposarcoma (FUS/TLS) gene mutations. METHODS: A consecutive series of 111 Japanese FALS pedigrees were screened for copper/zinc superoxide dismutase 1 (SOD1) and FUS/TLS gene mutations. Clinical data, including onset age, onset site, disease duration, and extramotor symptoms, were collected. RESULTS: Nine different FUS/TLS mutations were found in 12 pedigrees. Most of the patients with FUS/TLS-linked FALS demonstrated early onset in the brainstem/upper cervical region, and relatively short disease duration. A few mutations exhibited phenotypes that were distinct from typical cases. Frontotemporal dementia was present in 1 patient. CONCLUSIONS: This study revealed a characteristic phenotype in FUS/TLS-linked FALS patients in Japan. FUS/TLS screening is recommended in patients with FALS with this phenotype. Muscle Nerve 54: 398-404, 2016.

  147. 近位筋優位の筋力低下を呈したFUS/TLS遺伝子変異を伴う家族性ALS(ALS6)の一例

    江浦 信之, 泉 哲石, 桐山 敬生, 島倉 奈緒子, 鈴木 直輝, 加藤 昌昭, 杉江 和馬, 青木 正志, 上野 聡

    臨床神経学　56　(7)　528-528　2016/07

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  148. Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort

    Naoki Suzuki

    Neurobiology of Aging　2016

    DOI： 10.1016/J.NEUROBIOLAGING.2015.11.030 　

  149. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). International-journal Peer-reviewed

    Daniel J Klionsky, Kotb Abdelmohsen, Akihisa Abe, Md Joynal Abedin, Hagai Abeliovich, Abraham Acevedo Arozena, Hiroaki Adachi, Christopher M Adams, Peter D Adams, Khosrow Adeli, Peter J Adhihetty, Sharon G Adler, Galila Agam, Rajesh Agarwal, Manish K Aghi, Maria Agnello, Patrizia Agostinis, Patricia V Aguilar, Julio Aguirre-Ghiso, Edoardo M Airoldi, Slimane Ait-Si-Ali, Takahiko Akematsu, Emmanuel T Akporiaye, Mohamed Al-Rubeai, Guillermo M Albaiceta, Chris Albanese, Diego Albani, Matthew L Albert, Jesus Aldudo, Hana Algül, Mehrdad Alirezaei, Iraide Alloza, Alexandru Almasan, Maylin Almonte-Beceril, Emad S Alnemri, Covadonga Alonso, Nihal Altan-Bonnet, Dario C Altieri, Silvia Alvarez, Lydia Alvarez-Erviti, Sandro Alves, Giuseppina Amadoro, Atsuo Amano, Consuelo Amantini, Santiago Ambrosio, Ivano Amelio, Amal O Amer, Mohamed Amessou, Angelika Amon, Zhenyi An, Frank A Anania, Stig U Andersen, Usha P Andley, Catherine K Andreadi, Nathalie Andrieu-Abadie, Alberto Anel, David K Ann, Shailendra Anoopkumar-Dukie, Manuela Antonioli, Hiroshi Aoki, Nadezda Apostolova, Saveria Aquila, Katia Aquilano, Koichi Araki, Eli Arama, Agustin Aranda, Jun Araya, Alexandre Arcaro, Esperanza Arias, Hirokazu Arimoto, Aileen R Ariosa, Jane L Armstrong, Thierry Arnould, Ivica Arsov, Katsuhiko Asanuma, Valerie Askanas, Eric Asselin, Ryuichiro Atarashi, Sally S Atherton, Julie D Atkin, Laura D Attardi, Patrick Auberger, Georg Auburger, Laure Aurelian, Riccardo Autelli, Laura Avagliano, Maria Laura Avantaggiati, Limor Avrahami, Suresh Awale, Neelam Azad, Tiziana Bachetti, Jonathan M Backer, Dong-Hun Bae, Jae-Sung Bae, Ok-Nam Bae, Soo Han Bae, Eric H Baehrecke, Seung-Hoon Baek, Stephen Baghdiguian, Agnieszka Bagniewska-Zadworna, Hua Bai, Jie Bai, Xue-Yuan Bai, Yannick Bailly, Kithiganahalli Narayanaswamy Balaji, Walter Balduini, Andrea Ballabio, Rena Balzan, Rajkumar Banerjee, Gábor Bánhegyi, Haijun Bao, Benoit Barbeau, Maria D Barrachina, Esther Barreiro, Bonnie Bartel, Alberto Bartolomé, Diane C Bassham, Maria Teresa Bassi, Robert C Bast Jr, Alakananda Basu, Maria Teresa Batista, Henri Batoko, Maurizio Battino, Kyle Bauckman, Bradley L Baumgarner, K Ulrich Bayer, Rupert Beale, Jean-François Beaulieu, George R Beck Jr, Christoph Becker, J David Beckham, Pierre-André Bédard, Patrick J Bednarski, Thomas J Begley, Christian Behl, Christian Behrends, Georg Mn Behrens, Kevin E Behrns, Eloy Bejarano, Amine Belaid, Francesca Belleudi, Giovanni Bénard, Guy Berchem, Daniele Bergamaschi, Matteo Bergami, Ben Berkhout, Laura Berliocchi, Amélie Bernard, Monique Bernard, Francesca Bernassola, Anne Bertolotti, Amanda S Bess, Sébastien Besteiro, Saverio Bettuzzi, Savita Bhalla, Shalmoli Bhattacharyya, Sujit K Bhutia, Caroline Biagosch, Michele Wolfe Bianchi, Martine Biard-Piechaczyk, Viktor Billes, Claudia Bincoletto, Baris Bingol, Sara W Bird, Marc Bitoun, Ivana Bjedov, Craig Blackstone, Lionel Blanc, Guillermo A Blanco, Heidi Kiil Blomhoff, Emilio Boada-Romero, Stefan Böckler, Marianne Boes, Kathleen Boesze-Battaglia, Lawrence H Boise, Alessandra Bolino, Andrea Boman, Paolo Bonaldo, Matteo Bordi, Jürgen Bosch, Luis M Botana, Joelle Botti, German Bou, Marina Bouché, Marion Bouchecareilh, Marie-Josée Boucher, Michael E Boulton, Sebastien G Bouret, Patricia Boya, Michaël Boyer-Guittaut, Peter V Bozhkov, Nathan Brady, Vania Mm Braga, Claudio Brancolini, Gerhard H Braus, José M Bravo-San Pedro, Lisa A Brennan, Emery H Bresnick, Patrick Brest, Dave Bridges, Marie-Agnès Bringer, Marisa Brini, Glauber C Brito, Bertha Brodin, Paul S Brookes, Eric J Brown, Karen Brown, Hal E Broxmeyer, Alain Bruhat, Patricia Chakur Brum, John H Brumell, Nicola Brunetti-Pierri, Robert J Bryson-Richardson, Shilpa Buch, Alastair M Buchan, Hikmet Budak, Dmitry V Bulavin, Scott J Bultman, Geert Bultynck, Vladimir Bumbasirevic, Yan Burelle, Robert E Burke, Margit Burmeister, Peter Bütikofer, Laura Caberlotto, Ken Cadwell, Monika Cahova, Dongsheng Cai, Jingjing Cai, Qian Cai, Sara Calatayud, Nadine Camougrand, Michelangelo Campanella, Grant R Campbell, Matthew Campbell, Silvia Campello, Robin Candau, Isabella Caniggia, Lavinia Cantoni, Lizhi Cao, Allan B Caplan, Michele Caraglia, Claudio Cardinali, Sandra Morais Cardoso, Jennifer S Carew, Laura A Carleton, Cathleen R Carlin, Silvia Carloni, Sven R Carlsson, Didac Carmona-Gutierrez, Leticia Am Carneiro, Oliana Carnevali, Serena Carra, Alice Carrier, Bernadette Carroll, Caty Casas, Josefina Casas, Giuliana Cassinelli, Perrine Castets, Susana Castro-Obregon, Gabriella Cavallini, Isabella Ceccherini, Francesco Cecconi, Arthur I Cederbaum, Valentín Ceña, Simone Cenci, Claudia Cerella, Davide Cervia, Silvia Cetrullo, Hassan Chaachouay, Han-Jung Chae, Andrei S Chagin, Chee-Yin Chai, Gopal Chakrabarti, Georgios Chamilos, Edmond Yw Chan, Matthew Tv Chan, Dhyan Chandra, Pallavi Chandra, Chih-Peng Chang, Raymond Chuen-Chung Chang, Ta Yuan Chang, John C Chatham, Saurabh Chatterjee, Santosh Chauhan, Yongsheng Che, Michael E Cheetham, Rajkumar Cheluvappa, Chun-Jung Chen, Gang Chen, Guang-Chao Chen, Guoqiang Chen, Hongzhuan Chen, Jeff W Chen, Jian-Kang Chen, Min Chen, Mingzhou Chen, Peiwen Chen, Qi Chen, Quan Chen, Shang-Der Chen, Si Chen, Steve S-L Chen, Wei Chen, Wei-Jung Chen, Wen Qiang Chen, Wenli Chen, Xiangmei Chen, Yau-Hung Chen, Ye-Guang Chen, Yin Chen, Yingyu Chen, Yongshun Chen, Yu-Jen Chen, Yue-Qin Chen, Yujie Chen, Zhen Chen, Zhong Chen, Alan Cheng, Christopher Hk Cheng, Hua Cheng, Heesun Cheong, Sara Cherry, Jason Chesney, Chun Hei Antonio Cheung, Eric Chevet, Hsiang Cheng Chi, Sung-Gil Chi, Fulvio Chiacchiera, Hui-Ling Chiang, Roberto Chiarelli, Mario Chiariello, Marcello Chieppa, Lih-Shen Chin, Mario Chiong, Gigi Nc Chiu, Dong-Hyung Cho, Ssang-Goo Cho, William C Cho, Yong-Yeon Cho, Young-Seok Cho, Augustine Mk Choi, Eui-Ju Choi, Eun-Kyoung Choi, Jayoung Choi, Mary E Choi, Seung-Il Choi, Tsui-Fen Chou, Salem Chouaib, Divaker Choubey, Vinay Choubey, Kuan-Chih Chow, Kamal Chowdhury, Charleen T Chu, 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Takanobu Otomo, Kinya Otsu, Jing-Hsiung James Ou, Tiago F Outeiro, Dong-Yun Ouyang, Hongjiao Ouyang, Michael Overholtzer, Michelle A Ozbun, P Hande Ozdinler, Bulent Ozpolat, Consiglia Pacelli, Paolo Paganetti, Guylène Page, Gilles Pages, Ugo Pagnini, Beata Pajak, Stephen C Pak, Karolina Pakos-Zebrucka, Nazzy Pakpour, Zdena Palková, Francesca Palladino, Kathrin Pallauf, Nicolas Pallet, Marta Palmieri, Søren R Paludan, Camilla Palumbo, Silvia Palumbo, Olatz Pampliega, Hongming Pan, Wei Pan, Theocharis Panaretakis, Aseem Pandey, Areti Pantazopoulou, Zuzana Papackova, Daniela L Papademetrio, Issidora Papassideri, Alessio Papini, Nirmala Parajuli, Julian Pardo, Vrajesh V Parekh, Giancarlo Parenti, Jong-In Park, Junsoo Park, Ohkmae K Park, Roy Parker, Rosanna Parlato, Jan B Parys, Katherine R Parzych, Jean-Max Pasquet, Benoit Pasquier, Kishore Bs Pasumarthi, Daniel Patschan, Cam Patterson, Sophie Pattingre, Scott Pattison, Arnim Pause, Hermann Pavenstädt, Flaminia Pavone, Zully Pedrozo, 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Xu Dong Zhang, Yan Zhang, Yang Zhang, Yanjin Zhang, Yingmei Zhang, Yunjiao Zhang, Mei Zhao, Wei-Li Zhao, Xiaonan Zhao, Yan G Zhao, Ying Zhao, Yongchao Zhao, Yu-Xia Zhao, Zhendong Zhao, Zhizhuang J Zhao, Dexian Zheng, Xi-Long Zheng, Xiaoxiang Zheng, Boris Zhivotovsky, Qing Zhong, Guang-Zhou Zhou, Guofei Zhou, Huiping Zhou, Shu-Feng Zhou, Xu-Jie Zhou, Hongxin Zhu, Hua Zhu, Wei-Guo Zhu, Wenhua Zhu, Xiao-Feng Zhu, Yuhua Zhu, Shi-Mei Zhuang, Xiaohong Zhuang, Elio Ziparo, Christos E Zois, Teresa Zoladek, Wei-Xing Zong, Antonio Zorzano, Susu M Zughaier

    Autophagy　12　(1)　1-222　2016

    DOI： 10.1080/15548627.2015.1100356 　

    ISSN： 1554-8627

  150. Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome. International-journal Peer-reviewed

    Hazuki Komuro, Naoko Sato, Ayaka Sasaki, Naoki Suzuki, Michiko Kano, Yukari Tanaka, Yumi Yamaguchi-Kabata, Motoyori Kanazawa, Hitoshi Warita, Masashi Aoki, Shin Fukudo

    PloS one　11　(1)　e0147817　2016

    DOI： 10.1371/journal.pone.0147817 　

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    BACKGROUND: Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients. METHODS: A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs) of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220) were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale. RESULTS: We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017) and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS), and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710) and two SNPs (rs2284217 and rs2284220) in strong linkage disequilibrium (D' > 0.90). We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion. CONCLUSION: Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH system are warranted.

  151. Associations between Single-Nucleotide Polymorphisms in Corticotropin-Releasing Hormone-Related Genes and Irritable Bowel Syndrome. International-journal Peer-reviewed

    Ayaka Sasaki, Naoko Sato, Naoki Suzuki, Michiko Kano, Yukari Tanaka, Motoyori Kanazawa, Masashi Aoki, Shin Fukudo

    PloS one　11　(2)　e0149322　2016

    DOI： 10.1371/journal.pone.0149322 　

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    UNLABELLED: Irritable bowel syndrome (IBS) is a common functional disorder with distinct features of stress-related pathophysiology. A key mediator of the stress response is corticotropin-releasing hormone (CRH). Although some candidate genes have been identified in stress-related disorders, few studies have examined CRH-related gene polymorphisms. Therefore, we tested our hypothesis that single-nucleotide polymorphisms (SNPs) in CRH-related genes influence the features of IBS. METHODS: In total, 253 individuals (123 men and 130 women) participated in this study. They comprised 111 IBS individuals and 142 healthy controls. The SNP genotypes in CRH (rs28364015 and rs6472258) and CRH-binding protein (CRH-BP) (rs10474485) were determined by direct sequencing and real-time polymerase chain reaction. The emotional states of the subjects were evaluated using the State-Trait Anxiety Inventory, Perceived Stress Scale, and the Self-rating Depression Scale. RESULTS: Direct sequencing of the rs28364015 SNP of CRH revealed no genetic variation among the study subjects. There was no difference in the genotype distributions and allele frequencies of rs6472258 and rs10474485 between IBS individuals and controls. However, IBS subjects with diarrhea symptoms without the rs10474485 A allele showed a significantly higher emotional state score than carriers. CONCLUSIONS: These results suggest that the CRH and CRH-BP genes have no direct effect on IBS status. However, the CRH-BP SNP rs10474485 has some effect on IBS-related emotional abnormalities and resistance to psychosocial stress.

  152. Sporadic Inclusion Body Myositis Manifesting as Isolated Muscle Weakness of the Finger Flexors Three Years after Disease Onset Peer-reviewed

    Yuichi Suwa, Naoki Suzuki, Temma Soga, Ryuhei Harada, Aya Shibui, Hiroshi Kuroda, Rumiko Izumi, Maki Tateyama, Ichiro Nakashima, Masahiro Sonoo, Masashi Aoki

    INTERNAL MEDICINE　55　(23)　3521-3524　2016

    DOI： 10.2169/internalmedicine.55.7285 　

    ISSN： 0918-2918

    eISSN： 1349-7235

  153. OX40 and IL-7 play synergistic roles in the homeostatic proliferation of effector memory CD4⁺ T cells. Peer-reviewed

    Yamaki S, Ine S, Kawabe T, Okuyama Y, Suzuki N, Soroosh P, Mousavi SF, Nagashima H, Sun SL, So T, Sasaki T, Harigae H, Sugamura K, Kudo H, Wada M, Nio M, Ishii N

    European journal of immunology　44　(10)　3015-3025　2014/10

    DOI： 10.1002/eji.201444701 　

    ISSN： 0014-2980

  154. [Sporadic inclusion body myositis and amyloid]. Peer-reviewed

    Masashi Aoki, Naoki Suzuki

    Brain and nerve = Shinkei kenkyu no shinpo　66　(7)　739-48　2014/07

    ISSN： 1881-6096

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown etiology and without effective treatment. While the etiology is still unknown, however, genetic factors, aging, life style, and environmental factors may be involved. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers and rimmed vacuoles, suggesting inflammation and degeneration co-exist as part of the pathomechanism. Recent studies implicate amyloid beta accumulation, defects of proteolysis, and immune system abnormalities. The clinical course is slow with chronic worsening. Diagnosis of sIBM is usually made 5 years after onset. Muscle weakness and atrophy in the quadriceps, wrist flexor and finger flexors are the typical neurological findings of sIBM. Dysphagia and asymmetric weakness are often found. Serum creatine kinase is usually below 2,000 IU/L. sIBM is generally refractory to current therapy, such as steroids or immunosuppressants. Elucidation of the pathomechanism of sIBM is the most important to therapy.

  155. An autopsy case involving a 12-year history of amyotrophic lateral sclerosis with CIDP-like polyneuropathy. Peer-reviewed

    Tetsuya Akaishi, Maki Tateyama, Kazuhiro Kato, Emiko Miura, Rumiko Izumi, Kaoru Endo, Naoto Sugeno, Naoki Suzuki, Toru Baba, Tatsuro Misu, Akio Kikuchi, Takafumi Hasegawa, Sachiko Konosu-Fukaya, Fumiyoshi Fujishima, Hiroyoshi Suzuki, Ichiro Nakashima, Masashi Aoki

    Internal medicine (Tokyo, Japan)　53　(12)　1371-5　2014

    DOI： 10.2169/internalmedicine.53.0774 　

    ISSN： 0918-2918

    eISSN： 1349-7235

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    Demyelinating polyneuropathy associated with amyotrophic lateral sclerosis (ALS) is quite rare. We herein present the case of a woman patient with a 12-year history of chronic inflammatory demyelinating polyneuropathy (CIDP)-like polyneuropathy who later developed bulbar palsy and respiratory failure. The autopsy findings revealed neuronal loss in the anterior horn and primary motor cortex with degeneration of the corticospinal tracts. Diffuse phosphorylated TAR DNA-binding protein of 43 kDa inclusions were observed in the anterior horn and cerebral cortices, including the temporal lobe. The final diagnosis was ALS with CIDP-like polyneuropathy. Compared with other reports of ALS with CIDP-like polyneuropathy, the present patient was younger and followed a relatively long clinical course, with no upper motor neuron signs.

  156. [Recent progress in diagnosis and pathomechanism of inclusion body myositis]. Peer-reviewed

    Masashi Aoki, Naoki Suzuki, Masaaki Kato, Hitoshi Warita

    Rinsho shinkeigaku = Clinical neurology　54　(12)　1115-8　2014

    DOI： 10.5692/clinicalneurol.54.1115 　

    ISSN： 0009-918X

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown etiology and without effective treatment. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers and rimmed vacuoles, suggesting inflammation and degeneration co-exist as part of the pathomechanism. We estimated the prevalence of sIBM in Japan is 1,000-1,500 in 2003 and an increase in the number of sIBM in Japan in the decade. TDP43 can be a whole mark of the muscle pathology of sIBM patients. Anti-cytosolic 5'-nucleotidase 1A (cN1A) can be a diagnostic marker of sIBM. Elucidation of the pathomechanism of sIBM is the most important to therapy. We'll also review the status of the therapeutics and clinical trials in sIBM.

  157. 筋萎縮性側索硬化症モデルラット徴小血管の壁細胞を標的とした運動ニューロン保障

    割田 仁, 水野 秀紀, 加藤 昌昭, 鈴木 直輝, 青木 正志

    臨床神経学　53　(12)　1638-1638　2013/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  158. Hereditary neuropathy with liability to pressure palsy emerging after hypothyroidism Peer-reviewed

    Naoki Suzuki

    Neurology and Clinical Neuroscience　1　(4)　160-161　2013/07

    DOI： 10.1111/NCN3.41 　

  159. Inflammatory demyelinating polyneuropathy with nephrotic syndrome: Report of a case and review of the literature Peer-reviewed

    Maki Tateyama, Ichiro Nakashima, Naoki Suzuki, Chihiro Kanaoka-Suzuki, Rina Takano, Hiroshi Sato, Susumu Kusunoki, Kazuo Fujihara, Yasuto Itoyama, Masashi Aoki

    Clinical and Experimental Neuroimmunology　4　(1)　79-88　2013/06

    DOI： 10.1111/cen3.12009 　

    ISSN： 1759-1961

  160. Familial amyotrophic lateral sclerosis with novel A4DSOD1mutation with late age at onset and rapid progressive course

    Hiroya Naruse, Atsushi Iwata, Yuji Takahashi, Kazuaki Ichihara, Satoshi Kamei, Masato Yamatoku, Toshikazu Hirayama, Naoki Suzuki, Masashi Aoki, Toji Miyagawa, Jun Shimizu, Shoji Tsuji, Jun Goto

    Neurology and Clinical Neuroscience　1　(1)　45-47　2013/01

    Publisher: Wiley

    DOI： 10.1002/ncn3.8 　

    ISSN： 2049-4173

  161. 両側腓腹部に限局した非進行性神経原性筋萎縮症を呈した孤発例の1例 Peer-reviewed

    原 賢寿, 竪山 真規, 鈴木 直輝, 柴野 健, 田中 恵子, 石黒 英明

    臨床神経学　53　551-554　2013

  162. [Sporadic case of non-progressive neurogenic muscular atrophy localized in both calf muscles]. Peer-reviewed

    Kenju Hara, Maki Tateyama, Naoki Suzuki, Ken Shibano, Keiko Tanaka, Hideaki Ishiguro

    Rinsho shinkeigaku = Clinical neurology　53　(7)　551-4　2013

    DOI： 10.5692/clinicalneurol.53.551 　

    ISSN： 0009-918X

    eISSN： 1882-0654

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    A 60-year-old woman was admitted to our hospital because of difficulty in standing on her toes. Neurological examination showed muscle weakness in both calf muscles. Her serum creatine kinase (CK) level was slightly elevated. MRI revealed hyper-intense signals localized in both the gastrocnemius and soleus muscles. Histological examinations of biopsied muscle specimens showed a marked variation in fiber size, small angular fibers, and hypertrophic and splitting fibers, but no muscle fiber necrosis or regeneration or inflammatory cell infiltration. ATPase stained sections showed small grouped atrophy of type 1 fibers. NADH-TR stained sections showed target/targetoid fibers predominantly in type 1 fibers. Dysferlin immunoreactivity was normal. Follow-up clinical evaluation for one year showed no progression. This patient was diagnosed as having an unknown type of spinal muscular atrophy or benign calf amyotrophy. Sporadic cases characterized by elderly-onset, neurogenic muscular atrophy localized in both calf muscles, and non-progressive course are extremely rare in Japan.

  163. 日本人家族性ALSにおける遺伝子変異と臨床型の検討

    加藤 昌昭, 割田 仁, 鈴木 直輝, 島倉 奈緒子, 青木 正志

    臨床神経学　52　(12)　1601-1601　2012/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  164. 筋萎縮性側索硬化症モデルラット新生グリア細胞が形成する脊髄微小環境

    割田 仁, 加藤 昌昭, 鈴木 直輝, 水野 秀紀, 青木 正志

    臨床神経学　52　(12)　1603-1603　2012/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  165. Lower motor neuron disease caused by a novel FUS/TLS gene frameshift mutation. International-journal Peer-reviewed

    Makoto Hara, Masayuki Minami, Satoshi Kamei, Naoki Suzuki, Masaaki Kato, Masashi Aoki

    Journal of neurology　259　(10)　2237-9　2012/10

    DOI： 10.1007/s00415-012-6542-2 　

    ISSN： 0340-5354

  166. Two cases of elderly-onset hereditary neuropathy with liability to pressure palsy manifesting bilateral peroneal nerve palsies. International-journal Peer-reviewed

    Norihiko Kawaguchi, Naoki Suzuki, Maki Tateyama, Yoshiki Takai, Tatsuro Misu, Ichiro Nakashima, Yasuto Itoyama, Masashi Aoki

    Case reports in neurology　4　(3)　149-55　2012/09

    DOI： 10.1159/000342132 　

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    Hereditary neuropathy with liability to pressure palsy (HNPP) is characterized by recurrent focal neuropathies, which usually become symptomatic in the second or third decade of life. However, clinical phenotypic heterogeneity among patients with HNPP has recently been reported. Certain patients show polyneuropathy-type diffuse nerve injuries, whereas others remain asymptomatic at older ages. We present two cases of elderly-onset bilateral peroneal nerve palsies with diffuse muscle weakness in the lower limbs and glove-and-stocking type sensory disturbance. Both patients were diagnosed with HNPP by genetic analyses that detected deletions of chromosome 17p11.2 in peripheral myelin protein 22 genes. Their clinical courses suggested that the Japanese sitting style termed 'seiza', a way of sitting on the floor with the lower legs crossed under the thighs, was a precipitating factor for the bilateral peroneal nerve palsies.

  167. [Sporadic inclusion body myositis in Japan]. Peer-reviewed

    Masashi Aoki, Naoki Suzuki

    Nihon rinsho. Japanese journal of clinical medicine　70　(5)　895-906　2012/05

    ISSN： 0047-1852

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    Sporadic inclusion body myositis (sIBM), the most common form of myopathy with inflammation in those over the age of 50 in Western countries, is an intractable and progressive skeletal muscle disease of unknown cause and without effective treatment. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers and rimmed vacuoles, suggesting inflammation and degeneration are co-existed in the pathogenesis. We estimated the prevalence of sIBM in Japan is 9.83 per million in 2003 and an increase in the number of sIBM in Japan in the decade. In this review, we discuss the diagnostic criteria sIBM in Japan, and describe available treatments and promising new therapeutic strategies. We also provide an update on the current understanding of sIBM pathogenesis.

  168. Continuous administration of poloxamer 188 reduces overload-induced muscular atrophy in dysferlin-deficient SJL mice. International-journal Peer-reviewed

    Naoki Suzuki, Tetsuya Akiyama, Toshiaki Takahashi, Hazuki Komuro, Hitoshi Warita, Maki Tateyama, Yasuto Itoyama, Masashi Aoki

    Neuroscience research　72　(2)　181-6　2012/02

    DOI： 10.1016/j.neures.2011.10.005 　

    ISSN： 0168-0102

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    Dysferlin-deficient SJL mice are commonly used to study dysferlinopathy. We demonstrated that poloxamer 188 (P188), a membrane sealant, is effective in reducing the loss of muscle mass in SJL mice when administered using an osmotic pump for 6 weeks. We did not observe significant changes over a 2-week administration period, suggesting that longthier observation is necessary to determine the effectiveness of P188. We also examined exercise endurance in P188-administered SJL mice using a rolling cage. Phosphorylated p38 was found to be reduced in P188-administered SJL mice; additionally, using microarray analysis, we found diminished expression of atrogin-1, an E3 ubiquitin ligase, as the effector of muscular atrophy. Chronic infusion of P188 to dysferlin-deficient SJL mice reduced muscular atrophy, and administering p38 and atrogin-1 in the gastrocnemius muscle improved its motor function. These results provide a basis for potential treatments for dysferlin-deficient skeletal muscle fibers.

  169. An autopsy case of a dysferlinopathy patient with cardiac involvement. International-journal Peer-reviewed

    Naoki Suzuki, Toshiaki Takahashi, Yasushi Suzuki, Koichi Narikawa, Sonoko Kudo, Hiroyoshi Suzuki, Maki Tateyama, Masashi Aoki

    Muscle & nerve　45　(2)　298-9　2012/02

    DOI： 10.1002/mus.22247 　

    ISSN： 0148-639X

  170. Corticotropin-releasing hormone receptor 1 gene variants in irritable bowel syndrome. International-journal Peer-reviewed

    Naoko Sato, Naoki Suzuki, Ayaka Sasaki, Emiko Aizawa, Takeshi Obayashi, Motoyori Kanazawa, Tomoko Mizuno, Michiko Kano, Masashi Aoki, Shin Fukudo

    PloS one　7　(9)　e42450　2012

    DOI： 10.1371/journal.pone.0042450 　

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    BACKGROUND: Corticotropin-releasing hormone (CRH) acts mainly via the CRH receptor 1 (CRH-R1) and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS). Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients. METHODS: A total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402) were genotyped. Subjects' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale. RESULTS: The TT genotype of rs7209436 (P = 0.01) and rs242924 (P = 0.02) was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms) and the T allele of rs7209436 (P = 0.008), T allele of rs242924 (P = 0.019), A allele of rs110402 (P = 0.047), and TAT haplocopies (P = 0.048). Negative emotion was not associated with the examined CRH-R1 SNPs. CONCLUSION: These findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.

  171. [Clinical genetics of amyotrophic lateral sclerosis in Japan: an update]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Masaaki Kato

    Rinsho shinkeigaku = Clinical neurology　52　(11)　844-7　2012

    DOI： 10.5692/clinicalneurol.52.844 　

    ISSN： 0009-918X

    eISSN： 1882-0654

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    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. In familial ALS kinders with mutations in the SOD1 gene, the age of onset of weakness varies greatly but the duration of illness appears to be characteristic to each mutation. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been discovered to be associated with familial ALS. In a Japanese family with familial ALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with ALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, and the average age of death was 37.2 years. Neuropathological examination revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. The frequency of a hexanucleotide repeat expansion in C9ORF72 with familial ALS has been estimated as approximately 5% in Japan, although the one Japanese patient was identified as a carrier of the C9ORF72 expansion carried the Finnish risk haplotype.

  172. [Clinical translation of hepatocyte growth factor for amyotrophic lateral sclerosis]. Peer-reviewed

    Hitoshi Warita, Masaaki Kato, Naoki Suzuki, Yasuto Itoyama, Masashi Aoki

    Rinsho shinkeigaku = Clinical neurology　52　(11)　1214-7　2012

    DOI： 10.5692/clinicalneurol.52.1214 　

    ISSN： 0009-918X

    eISSN： 1882-0654

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    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons. Approximately 20% of familial ALS cases are linked to mutations in Cu/Zn superoxide dismutase (SOD1) gene. Previously, we developed a transgenic rat model of ALS overexpressing mutant SOD1 protein. The rat model facilitates preclinical ALS research employing various therapeutic approaches such as intrathecal administration, cell transplantation, and viral vector-mediated gene transduction to the affected central nervous system. Hepatocyte growth factor (HGF) is a pleiotropic growth factor and also a potent survival-promoting factor for motor neurons. To examine its therapeutic effect on ALS, we administered human recombinant HGF (hrHGF) to the transgenic ALS rats. In contrast with vehicle-treated rats, continuous intrathecal infusion of hrHGF attenuated spinal motor neuron degeneration and prolonged the duration of the disease, even with administration from the onset of symptoms. To translate the strategy to human treatment, we performed dose-finding and safety studies using non-human primate model of contusive cervical spinal cord injury. Introducing exogenous HGF protein also revealed a distinct therapeutic effect with functional recovery. Given the therapeutic potential of hrHGF on ALS, we started a novel phase I clinical trial for ALS patients in Tohoku University Hospital.

  173. FUS/TLS遺伝子異常に伴う日本人家族性ALSにおける遺伝子変異と臨床型、病理に関する検討

    青木 正志, 鈴木 直輝, 割田 仁, 加藤 昌昭, 水野 秀紀, 島倉 奈緒子, 今野 秀彦, 加藤 信介, 糸山 泰人

    臨床神経学　51　(12)　1225-1225　2011/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  174. 筋萎縮性側索硬化症モデルラットにおける骨格筋再生

    割田 仁, 水野 秀紀, 鈴木 直輝, 糸山 泰人, 青木 正志

    臨床神経学　51　(12)　1317-1317　2011/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  175. 日本人三好型遠位型筋ジストロフィーの遺伝子変異の特徴と自然歴 肢帯型筋ジストロフィー2B型との比較 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 小野寺 宏, 西野 一三, 糸山 泰人

    臨床神経学　51　(12)　1301-1301　2011/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  176. [Amyotrophic lateral sclerosis (ALS) and fused in sarcoma/translocated in liposarcoma (FUS/TLS)]. Peer-reviewed

    Naoki Suzuki, Masashi Aoki

    Nihon rinsho. Japanese journal of clinical medicine　69 Suppl 10 Pt 2　(Pt 2)　389-93　2011/12

    ISSN： 0047-1852

  177. [Inclusion body myositis]. Peer-reviewed

    Naoki Suzuki, Masashi Aoki

    Brain and nerve = Shinkei kenkyu no shinpo　63　(11)　1205-15　2011/11

    ISSN： 1881-6096

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown cause that has no curative treatment. Its prevalence varies among countries and ethnic groups. The clinical course is slow and chronic worsening. Diagnosis of sIBM is usually made 5 years after onset. Muscle weakness and atrophy in the quadriceps, wrist flexor, and finger flexors are the typical neurological findings of sIBM. Dysphagia and asymmetric weakness are often found as well. Serum creatine kinase is usually below 2,000 IU/L. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers, and rimmed vacuoles, suggesting that inflammation and degeneration are coexist in the pathomechanism. The etiology of sIBM is still unknown; however, genetic factors, aging, lifestyle, and environmental factors may be involved. Recent studies have implicated amyloid beta accumulation, defects of proteolysis, and immune system abnormalities in the pathomechanism of sIBM. sIBM is generally refractory to current therapy, such as steroids or immunosuppressants. Recently, alemtuzumab, which targets T cells, has resulted in improvement in quantitative muscle strength testing. New strategies to induce proteolysis and autophagy, accelerate muscle regeneration, inhibit myostatin, and modulate inflammatory cells are promising. Elucidation of the pathomechanism of sIBM is the key to developing effective therapies.

  178. [Pathomechanism and prevalence of sporadic inclusion body myositis (sIBM)]. Peer-reviewed

    Naoki Suzuki, Maki Tateyama, Hitoshi Warita, Rumiko Izumi, Ichizo Nishino, Masashi Aoki

    Rinsho shinkeigaku = Clinical neurology　51　(11)　964-6　2011/11

    DOI： 10.5692/clinicalneurol.51.964 　

    ISSN： 0009-918X

    eISSN： 1882-0654

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown cause and without effective treatment. The etiology of sIBM is still unknown, however genetic factors, aging, life styles, environmental factors may be involved. sIBM is generally refractory to current therapy, such as steroid or immunosuppressants. To elucidate the pathomechanism of sIBM is the most important way to make therapeutic approach. In this review we estimated the prevalence of sIBM in Japan and discuss the pathomechanism of sIBM.

  179. [Regenerative therapies for amyotrophic lateral sclerosis using hepatocyte growth factor]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Masaaki Kato, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology　51　(11)　1195-8　2011/11

    DOI： 10.5692/clinicalneurol.51.1195 　

    ISSN： 0009-918X

    eISSN： 1882-0654

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    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We have developed rats that express a human SOD1 transgene with two different ALS-associated mutations develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine both its protective effect on motor neurons and its therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to the transgenic rats at the onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. These results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.

  180. [Case of multiple sclerosis with "yes-yes" type head tremor]. Peer-reviewed

    Kei Omata, Naoki Suzuki, Rumiko Izumi, Mari Nagata, Shuhei Nishiyama, Ichiro Nakashima, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology　51　(4)　282-5　2011/04

    DOI： 10.5692/clinicalneurol.51.282 　

    ISSN： 0009-918X

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    A 32-year-old woman, who had developed head tremor and paresthesia of the right upper limb for several months, was admitted to our hospital The diagnosis of multiple sclerosis was made because the serial MRI showed multiple lesions in both the cerebral white matter and the cervical cord. Oligoclonal IgG band was positive. Her symptoms were improved by intravenous methylprednisolone and an antiepileptic drug (MEPM 1 g/day and CZP 1 mg/day). The head tremor was the so-called "yes-yes" type which shakes back and forth. Although this type of tremor has been considered to be developed by the lesions in the cerebellum, our patient seemed to develop the tremor by cervical cord lesion. Further investigation is needed to confirm the association of the head tremor and the cervical lesions in MS.

  181. Herpes labialis in multiple sclerosis with a trigeminal lesion. Peer-reviewed

    Naoki Suzuki, Hideki Mizuno, Ichiro Nakashima, Yasuto Itoyama

    Internal medicine (Tokyo, Japan)　50　(3)　259-259　2011

    DOI： 10.2169/internalmedicine.50.4278 　

    ISSN： 0918-2918

    eISSN： 1349-7235

  182. A case of late onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency manifesting as recurrent rhabdomyolysis and acute renal failure. Peer-reviewed

    Rumiko Izumi, Naoki Suzuki, Mari Nagata, Takafumi Hasegawa, Yu Abe, Yuka Saito, Hiroshi Mochizuki, Maki Tateyama, Masashi Aoki

    Internal medicine (Tokyo, Japan)　50　(21)　2663-8　2011

    DOI： 10.2169/internalmedicine.50.5172 　

    ISSN： 0918-2918

    eISSN： 1349-7235

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    We report an adult case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by episodic recurrent rhabdomyolysis and acute renal failure after the age of 46. Muscle biopsy revealed lipid storage myopathy and the finding of serum acylcarnitine and urine organic acid analyses were consistent with MADD. A compound heterozygous mutation was identified in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, including a novel missense mutation, which confirmed the diagnosis of MADD. After administration of riboflavin and L-carnitine, the muscle weakness and fatigability gradually improved. Acylcarnitine and urine organic acid were also normalized after supplementation. Thus, MADD should be included in one of the differential diagnoses for adult recurrent rhabdomyolysis. Gene analysis is useful to confirm the diagnosis, and early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD.

  183. Neuromyelitis optica preceded by hyperCKemia episode. International-journal Peer-reviewed

    Joseph S Jeret, Naoki Suzuki, Toshiyuki Takahashi, Kazuo Fujihara

    Neurology　75　(24)　2253 author reply 2253-4　2010/12/14

    DOI： 10.1212/WNL.0b013e3181fac76b 　

  184. 若年発症・急速進行・好塩基性封入体を特徴としFUS遺伝子変異を伴う家族性ALSの5家系

    青木 正志, 鈴木 直輝, 割田 仁, 加藤 昌昭, 水野 秀紀, 島倉 奈緒子, 秋山 徹也, 今野 秀彦, 糸山 泰人

    臨床神経学　50　(12)　1084-1084　2010/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  185. 微小血管新生促進によるALSモデルラット神経保護の試み

    割田 仁, 青木 正志, 水野 秀紀, 鈴木 直輝, 船越 洋, 中村 敏一, 糸山 泰人

    臨床神経学　50　(12)　1198-1198　2010/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  186. 日本人のdysferlin遺伝子変異の確定した肢帯型筋ジストロフィー2B型の特徴 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学　50　(12)　1088-1088　2010/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  187. Neuronal NOS is dislocated during muscle atrophy in amyotrophic lateral sclerosis. International-journal Peer-reviewed

    Naoki Suzuki, Hideki Mizuno, Hitoshi Warita, Shin'ichi Takeda, Yasuto Itoyama, Masashi Aoki

    Journal of the neurological sciences　294　(1-2)　95-101　2010/07/15

    DOI： 10.1016/j.jns.2010.03.022 　

    ISSN： 0022-510X

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    Previously, we demonstrated that neuronal nitric oxide synthase (nNOS) is activated and promotes muscle atrophy in skeletal muscle during tail suspension, a model of unloading and denervation. Here, we examined patients with amyotrophic lateral sclerosis (ALS) and mutant (H46R) SOD1 transgenic (Tg) mice model using immunohistochemistry, Western blotting and real time PCR. We found cytoplasmic nNOS staining of angulated muscle fibers in patients with ALS. We also examined mutant SOD1 Tg mice and found cytoplasmic nNOS staining even before the onset of clinical muscle atrophy. In the Tg mice, nNOS was largely extracted with 100 mM NaCl and barely detected in the pellet fraction, suggesting fragile anchoring of nNOS to the sarcolemma. We also showed an elevated expression of atrogin-1, key molecules in muscle atrophy at the end stage. A common nNOS dislocation/atrogin-1/muscle atrophy pathway among tail suspension, denervation and ALS is suggested. nNOS modulation therapy may be beneficial in several types of muscle atrophy.

  188. Reply from the authors

    Suzuki, N., Takahashi, T., Fujihara, K.

    Neurology　75　(24)　2010

    DOI： 10.1212/WNL.0b013e3181fac76b 　

  189. Rapid screening for Japanese dysferlinopathy by fluorescent primer extension. Peer-reviewed

    Saori Hayashi, Yutaka Ohsawa, Toshiaki Takahashi, Naoki Suzuki, Tadashi Okada, Mitsue Rikimaru, Tatsufumi Murakami, Masashi Aoki, Yoshihide Sunada

    Internal medicine (Tokyo, Japan)　49　(24)　2693-6　2010

    DOI： 10.2169/internalmedicine.49.3771 　

    ISSN： 0918-2918

    eISSN： 1349-7235

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    OBJECTIVE: Mutations in the dysferlin gene cause limb-girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy (MM), which are collectively named dysferlinopathy. Dysferlinopathy is the most frequent type of LGMD in the Japanese population. Molecular genetic analysis is essential for the diagnosis of dysferlinopathy because of its variable immunohistochemical patterns of biopsied muscles, including patterns similar to normal controls. The analysis of the entire dysferlin gene however, is time-consuming and laborious; therefore a simple and rapid screening method to detect hot spot mutations in the dysferlin gene is essential for the diagnosis of dysferlinopathy. METHODS: We previously showed that 4 mutations, c.937+1G>A, c.1566C>G, c.2997G>T and c.3373delG account for 50% of all the mutations identified in Japanese dysferlinopathy patients. We performed a one-tube multiplex PCR, followed by extension of primers for each mutation with a fluorescence-labeled dideoxynucleotide to screen the 4 hot spot mutations. RESULTS: The multiplex primer-extension reaction was developed on samples of known mutations. The extension products were represented as 4 different peaks that corresponded to a mutated nucleotide on electropherogram. Using the developed screening method, we were able to detect mutations in these hot spots in 3 samples out of 8 clinically suspected LGMD2B/MM patients in only approximately 8 hours. These 3 cases were definitely diagnosed as LGMD2B/MM by exonic sequencing. CONCLUSION: We have developed a simple and rapid screening method which could facilitate the definitive diagnosis of dysferlinopathy, contributing to an understanding of the genotype-phenotype correlations for dysferlinopathy.

  190. 筋萎縮性側索硬化症マウスに対する一酸化窒素合成酵素阻害剤による治療の検討

    鈴木 直輝, 青木 正志, 割田 仁, 水野 秀紀, 武田 伸一, 糸山 泰人

    臨床神経学　49　(12)　1020-1020　2009/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  191. 肢帯型筋ジストロフィー2B型におけるG3370T変異と臨床経過 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学　49　(12)　1053-1053　2009/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  192. ALS治療法開発の将来 神経栄養因子によるALSの治療戦略

    青木 正志, 割田 仁, 鈴木 直輝, 糸山 泰人

    臨床神経学　49　(11)　814-817　2009/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  193. [Development of motor neuron restorative therapy in amyotrophic lateral sclerosis using hepatocyte growth factor]. Peer-reviewed

    Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology　49　(11)　814-7　2009/11

    DOI： 10.5692/clinicalneurol.49.814 　

    ISSN： 0009-918X

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    Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. Mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene have been recently discovered to be associated with familial ALS. We found FUS/TLS mutations in familial ALS cases in Japan. Even in Asian races, ALS with FUS/TLS mutations may have common characteristics of early onset, rapid progress, high penerence trait. We developed rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine its both protective effect on motor neurons and therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in ALS rats. In addition, HGF is capable of reducing astrocytosis and microglial accumulation, and thus supports the attention of a glial-dependent mechanism of ALS progression. These results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.

  194. Dorsal-roots enhancement and Wallerian degeneration of dorsal cord in the patient of acute sensory ataxic neuropathy. International-journal Peer-reviewed

    Kaoru Endo, Naoki Suzuki, Tatsuro Misu, Masashi Aoki, Yasuto Itoyama

    Journal of neurology　256　(10)　1765-6　2009/10

    DOI： 10.1007/s00415-009-5186-3 　

    ISSN： 0340-5354

  195. [A marked decrease of orexin in the cerebrospinal fluid in a patient with myotonic dystrophy type 1 showing an excessive daytime sleepiness]. Peer-reviewed

    Tomoaki Iwata, Naoki Suzuki, Hideki Mizuno, Ichiro Nakashima, Takashi Kanbayashi, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology　49　(7)　437-9　2009/07

    DOI： 10.5692/clinicalneurol.49.437 　

    ISSN： 0009-918X

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    Excessive daytime somnolence is one of the common complaints in patients with myotonic dystrophy. Here we report a 60-year-old female case of myotonic dystrophy type 1 with narcolepsy due to medical condition. The size of the CTG repeat in the 3' untranslated region of the DMPK gene was 1,800-2,400 repeats. Brain MRI was normal. Polysomnography revealed sleep apnea and chronic alveolar hypoventilation. Multiple sleep latency tests revealed normal sleep latencies and sleep onset REM was not observed. Orexin/hypocretin in the cerebrospinal fluid was markedly decreased to an undetectable level. Such sleep-related disorders may worsen the quality of life and possibly cause sudden death in patients with myotonic dystrophy. Narcolepsy associated with myotonic dystrophy should be evaluated appropriately.

  196. Short Term Efficacy of Thoracoscopic Thymectomy in Senile Onset Myasthenia Gravis Peer-reviewed

    Yoshiki Takai, Naoki Suzuki, Ichiro Nakashima, Kazuo Fujihara, Yasuto Itoyama

    NEUROLOGY　72　(11)　A54-A54　2009/03

    ISSN： 0028-3878

  197. Elevated serum aldolase activity in a patient of non-eosinophilic myofasciitis and synovitis with perifascicular atrophy Peer-reviewed

    Hirohiko Ono, Naoki Suzuki, Hideki Mizuno, Maki Tateyama, Masashi Aoki, Yasuto Itoyama

    Clinical Neurology　49　(2-3)　119-122　2009/02

    DOI： 10.5692/clinicalneurol.49.119 　

    ISSN： 0009-918X

  198. Intravenous immunoglobulin treatment successfully improved subacute progressive polyradiculoneuropathy with polyclonal gammopathy. Peer-reviewed

    Kaoru Endo, Naoki Suzuki, Taro Ikenishi, Masashi Aoki, Yasuto Itoyama

    Internal medicine (Tokyo, Japan)　48　(23)　2037-9　2009

    DOI： 10.2169/internalmedicine.48.2545 　

    ISSN： 0918-2918

    eISSN： 1349-7235

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    The present case was an elderly man with a history of gastric cancer, diffuse biliary duct stenosis and liver cirrhosis. He had markedly elevated IgG, suggesting chronic infection or inflammatory changes in the biliary duct. He developed weakness in his arms and became unable to use his hands within one month and 2 weeks later, he had difficulty walking. Based on his progressive disease course, elevated serum IgG, nerve conduction study and enhanced MRI findings, we diagnosed him as suffering from immune-mediated subacute polyradiculoneuropathy with polyclonal gammopathy, which might be related to Guillain-Barré syndrome. Intravenous immunoglobulin (IVIg) was dramatically effective in this patient. In the follow-up 6 months later he was stable and could walk without a cane. Even in patients with polyclonal gammopathy in chronic inflammatory disease of another organ, IVIg may be effective and beneficial for the patients's quality of life.

  199. 日本人のdysferlin遺伝子変異の確定した肢帯型筋ジストロフィーの臨床経過 Peer-reviewed

    高橋 俊明, 青木 正志, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学　48　(12)　1232-1232　2008/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  200. [Case of Neuro-Behçet disease resembling bacterial meningitis]. Peer-reviewed

    Masahiro Nezu, Naoki Suzuki, Hideki Mizuno, Yoshiki Takai, Tatsuro Misu, Masashi Aoki, Ichiro Nakashima, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology　48　(10)　750-3　2008/10

    DOI： 10.5692/clinicalneurol.48.750 　

    ISSN： 0009-918X

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    A 30-year-old man with intractable headache and high fever came to the emergency room. He presented skin eruption, aphtha, drowsiness (E3, V4, M6/GCS), meningeal sign, hyperreflexia, and bilateral papilloedema. He also showed pleocytosis (1,066/microl, polymorphonuclear cells predominantly) and pressure increase in CSF. WBC count and CRP were elevated. Two years before, he had meningeal sign, cervical myelitis, skin eruption, uveitis, and aphtha, and was diagnosed as Neuro-BehCet (NBD) disease. HLA-B52 and B55 were positive. We suspected recurrent NBD, but we couldn't exclude bacterial meningitis because of his symptoms and cell-pattern in CSF. We treated him with intravenous methylpredonisolone and antibiotics (MEPM 6 g/day and VCM 2 g/day). His symptoms dramatically improved within a few days. The rapid improvement might be attributed to the steroids. Furthermore, MRI FLAIR images showed multiple small high lesions in the brainstem, hemispheres, subcortical area, putamen and left cerebellar hemisphere. Serum procalcitonin was not increased. We diagnosed the recurrence of NBD retrospectively. Procalcitonin may be a useful marker for discrimination between meningitis due to NBD and septic meningitis.

  201. Downstream utrophin enhancer is required for expression of utrophin in skeletal muscle. International-journal Peer-reviewed

    Jun Tanihata, Naoki Suzuki, Yuko Miyagoe-Suzuki, Kazuhiko Imaizumi, Shin'ichi Takeda

    The journal of gene medicine　10　(6)　702-13　2008/06

    DOI： 10.1002/jgm.1190 　

    ISSN： 1099-498X

  202. Up-regulation of insulin-like growth factor-II receptor in reactive astrocytes in the spinal cord of amyotrophic lateral sclerosis transgenic rats. Peer-reviewed

    Byambasuren Dagvajantsan, Masashi Aoki, Hitoshi Warita, Naoki Suzuki, Yasuto Itoyama

    The Tohoku journal of experimental medicine　214　(4)　303-10　2008/04

    DOI： 10.1620/tjem.214.303 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  203. [Massive bleeding from tracheoarterial fistula in an amyotrophic lateral sclerosis patient treated with long-term invasive ventilation: an autopsy case report]. Peer-reviewed

    Kazuhiro Kato, Naoki Suzuki, Masashi Aoki, Hitoshi Warita, Kazutaka Jin, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology　48　(1)　60-2　2008/01

    DOI： 10.5692/clinicalneurol.48.60 　

    ISSN： 0009-918X

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    We report a 43-year-old woman with familial amyotrophic lateral sclerosis (FALS) who died of massive bleeding from a tracheoarterial fistula. Four years after the onset of the disease, she received invasive ventilation by tracheostomy because of respiratory failure. Four years and 7 months later, she showed an abrupt hemorrhage from the tracheostomy and died. The postmortem examination revealed a fistulous tract between the tracheal mucosal ulcer and the brachiocephalic trunk. The ulcer was in close proximity to the tracheostomy tube. In order to avoid such unexpected complications, we should observe the contact site between the tracheal mucosa and the tracheal tube in chronic tracheostomy patients.

  204. 肢帯型筋ジストロフィー2B型におけるdysferlin遺伝子変異と臨床型の関係 Peer-reviewed

    高橋 俊明, 青木 正志, 小野寺 好明, 鈴木 直輝, 竪山 真規, 吉岡 勝, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 小野寺 宏, 糸山 泰人

    臨床神経学　47　(12)　1056-1056　2007/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  205. A novel compound heterozygous dysferlin mutation in Miyoshi myopathy siblings responding to dantrolene Peer-reviewed

    H. Hattori, E. Nagata, Y. Oya, T. Takahashi, M. Aoki, D. Ito, N. Suzuki

    European Journal of Neurology　14　(11)　1288-1291　2007/11

    DOI： 10.1111/j.1468-1331.2007.01958.x 　

    ISSN： 1351-5101

    eISSN： 1468-1331

  206. Distal anterior compartment myopathy with early ankle contractures. International-journal Peer-reviewed

    Hiroshi Saito, Naoki Suzuki, Hideaki Ishiguro, Koichi Hirota, Yasuto Itoyama, Toshiaki Takahashi, Masashi Aoki

    Muscle & nerve　36　(4)　525-7　2007/10

    DOI： 10.1002/mus.20836 　

    ISSN： 0148-639X

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    Dysferlinopathies exhibit marked heterogeneity in the initial distribution of muscle involvement at the onset of the disease. We describe a Japanese patient with dysferlinopathy who exhibited distal anterior compartment myopathy (DACM) with early contractures of the ankle, whose pedigree included patients with two other types of dysferlinopathy. The existence of three phenotypes of dysferlinopathy in one pedigree is reported, indicating the involvement of molecules other than dysferlin in the pathogenesis.

  207. マウス尾部懸垂モデルにおけるnNOS/NOを介した筋萎縮の分子機構の解析

    鈴木 直輝, 本橋 紀夫, 上住 聡芳, 深田 宗一朗, 鈴木 友子, 武田 伸一

    臨床神経学　46　(12)　1044-1044　2006/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  208. Dysferlin遺伝子変異の確定した肢帯型筋ジストロフィー(LGMD)2B型の筋障害の分布 Peer-reviewed

    高橋 俊明, 青木 正志, 小野寺 好明, 鈴木 直輝, 竪山 真規, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 木村 格, 糸山 泰人

    臨床神経学　46　(12)　1120-1120　2006/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  209. Dysferlin遺伝子変異の確定した肢帯型筋ジストロフィー2B型の臨床型の解析 Peer-reviewed

    高橋 俊明, 青木 正志, 小野寺 好明, 鈴木 直輝, 竪山 真規, 今野 秀彦, 林 由起子, 西野 一三, 埜中 征哉, 齋藤 博, 木村 格, 糸山 泰人

    臨床神経学　45　(12)　1016-1016　2005/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  210. Expression profiling with progression of dystrophic change in dysferlin-deficient mice (SJL). International-journal Peer-reviewed

    Naoki Suzuki, Masashi Aoki, Yuji Hinuma, Toshiaki Takahashi, Yoshiaki Onodera, Aya Ishigaki, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Yasuto Itoyama

    Neuroscience research　52　(1)　47-60　2005/05

    DOI： 10.1016/j.neures.2005.01.006 　

    ISSN： 0168-0102

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    The SJL mouse is a model for human dysferlinopathy (limb-girdle muscular dystrophy type 2B and Miyoshi myopathy). We used cDNA microarrays to compare the expression profiles of 10,012 genes in control and SJL quadriceps femoris muscles in order to find genes involved in the degeneration and regeneration process and in dysferlin's functional network. Many genes involved in the process of muscle regeneration are observed to be up-regulated in SJL mice, including cardiac ankyrin repeated protein (CARP), Neuraminidase 2, interleukin-6, insulin-like growth factor-2 and osteopontin. We found the upregulation of S100 calcium binding proteins, neural precursor cell expressed, developmentally down-regulated gene 4-like (NEDD4L) with C2 domain, and intracellular protein traffic associated proteins (Rab6 and Rab2). These proteins have the potential to interact with dysferlin. We must reveal some other molecules which may work with dysferlin in order to clarify the pathological network of dysferlinopathy. This process may lead to future improvements in the therapy for human dysferlinopathy.

  211. [MR spectroscopy findings of a case of intravascular malignant lymphoma: usefulness for differential diagnosis]. Peer-reviewed

    Naoki Suzuki, Makiko Nagai, Aya Ishigaki, Yasushi Suzuki, Hiroshi Onodera, Eiji Jokura, Toshihiro Kumabe, Yusei Shiga, Yasuto Itoyama

    Rinsho shinkeigaku = Clinical neurology　43　(4)　180-2　2003/04

    ISSN： 0009-918X

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    We report a 49-year-old previously healthy woman with acute onset of decrease in attention, dysarthria and ataxia, accompanied by drowsiness. On admission, there were cloudness of consciousness, hallucination and left hemiparesis. Cerebrospinal fluid study revealed a cell count of 1/mm3, and the cytology was class I with a slight increase in protein. MRI of the brain performed on admission showed multiple gadolinium-enhanced lesions with a T2 weighted high intensity area in the cerebral white matter. At first the patient was diagnosed as acute disseminated encephalomyelitis (ADEM), and treated with methylprednisolon pulse therapy. Soon after, she showed transient clinical improvement, but her condition soon worsened. MR spectroscopy revealed elevated choline peak, decreased NAA peak and lactate peak, which indicated a neoplastic lesion. The brain biopsy disclosed diffuse intravascular lymphoma (IVL). MRS was useful in the differential diagnosis of IVL from ADEM.

  212. [A case of neuralgic amyotrophy manifesting bilateral anterior interosseous nerve syndrome]. Peer-reviewed

    Naoki Suzuki, Kazutaka Jin, Yusei Shiga, Hiroyuki Kato, Yasuto Itoyama

    No to shinkei = Brain and nerve　54　(7)　605-8　2002/07

    ISSN： 0006-8969

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    A 49-year-old woman acutely developed severe bilateral shoulder pain followed by weakness of the right shoulder girdle muscles. Within a few days, an inability to flex the terminal phalanges of the bilateral thumbs and index fingers emerged. Neurologic examination 1 month after the onset of symptoms showed atrophy of the right shoulder girdle muscles and mild decreased cutaneous sensation in the distribution of the right axillary nerve. Needle electromyography examination at this time showed fibrillation potentials in the right deltoid and bilateral flexor pollicus longus muscles. Recruitment of the right deltoid, supra- and infraspinatus muscles was reduced. Motor unit potentials in these muscles were of normal configuration. Nerve conduction studies in the upper limb were normal. She was diagnosed as neuralgic amyotrophy with bilateral anterior interosseous nerve syndrome. 4 months later, the muscles innervated by the bilateral anterior interosseous nerve improved in the muscle strength. Clinical features of this case were compatible with a mononeuropathy multiplex form of neuralgic amyotrophy associated with an autoimmune etiology. We think this case is important for speculating the pathogenesis of neuralgic amyotrophy. This case reminds us that patients with neuralgic amyotrophy sometimes demonstrate anterior interosseous nerve syndrome and most patients manifesting anterior interosseous nerve syndrome are patients with neuralgic amyotrophy.

Show all ︎Show first 5

Misc. 351

  1. Symposium7-3

    鈴木直輝

    体力科学　74　(1)　2025

    ISSN： 0039-906X

  2. 【iPS由来/直接誘導細胞を用いた神経疾患モデリングの最前線】iPS由来motor neuronを用いたALSの疾患モデリング

    鈴木 直輝

    Medical Science Digest　50　(2)　63-66　2024/02

    Publisher: (株)ニュー・サイエンス社

    ISSN： 1347-4340

  3. SOD1遺伝子変異による筋萎縮性側索硬化症の臨床的特徴

    中村亮一, 藤内玄規, 熱田直樹, 伊藤大輔, 勝野雅央, 和泉唯信, 平山剛久, 狩野修, 中里朋子, 服部信孝, 橋本里奈, 饗場郁子, 澁谷和幹, 桑原聡, 鈴木直輝, 青木正志, 織田雅也, 森田光哉, 道勇学, 祖父江元

    日本神経学会学術大会プログラム・抄録集　65th　2024

  4. 骨格筋の細胞膜修復を促進する新規ジスフェルリン結合タンパクの探索

    中村尚子, 鈴木直輝, 小野洋也, 菅野新一郎, 山中玲, 井泉瑠美子, 高橋俊明, 三宅克也, 青木正志

    日本分子生物学会年会プログラム・要旨集(Web)　47th　2024

  5. シアル酸補充療法の臨床試験

    鈴木直輝

    神経治療学(Web)　41　(6)　2024

    ISSN： 2189-7824

  6. 日本人ジスフェルリン異常症のミスセンスバリアントの特徴

    高橋俊明, 井泉瑠美子, 井泉瑠美子, 鈴木直輝, 鈴木直輝, 八木沼智香子, 島倉奈緒子, 中村尚子, 中村尚子, 下瀬川康子, 戸恒智子, 杉村容子, 佐々木陽彦, 吉岡勝, 馬場徹, 大泉英樹, 田中洋康, 割田仁, 新堀哲也, 長谷川隆文, 武田篤, 青木洋子, 青木正志

    国立病院総合医学会(Web)　78th　2024

  7. 私の治療 筋ジストロフィー

    鈴木直輝, 高橋俊明, 青木正志

    週刊日本医事新報　(5252)　2024

    ISSN： 0385-9215

  8. 筋細胞におけるメチオニンアミノペプチダーゼの役割

    長名シオン, 蔡承達, 鈴木直輝, 高田拓明, 金子雅希, 羽田克彦, 永富良一

    日本分子生物学会年会プログラム・要旨集(Web)　47th　2024

  9. Sporadic Inclusion Body Myositis

    青木正志, 井泉瑠美子, 鈴木直輝

    Brain and Nerve　76　(5)　0660-0670　2024

    Publisher: (株)医学書院

    DOI： 10.11477/mf.1416202657 　

    ISSN： 1881-6096

    eISSN： 1344-8129

  10. 運動ニューロン障害を合併した小脳性運動失調・感覚性ニューロパチー・前庭反射消失症候群(CANVAS)の一例

    志賀 太玖良, 吉田 幹裕, 鈴木 真紀, 池田 謙輔, 井泉 瑠美子, 鈴木 直輝, 割田 仁, 中島 一郎, 菅野 直人, 青木 正志

    臨床神経学　63　(12)　848-848　2023/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  11. 縁取り空胞を伴う遠位型ミオパチーを対象としたアセノイラミン酸の有効性

    青木 正志, 井泉 瑠美子, 鈴木 直輝

    BRAIN and NERVE: 神経研究の進歩　75　(10)　1149-1154　2023/10

    Publisher: (株)医学書院

    ISSN： 1881-6096

    eISSN： 1344-8129

  12. GNEミオパチーに対する経口アセノイラミン酸による治療開発

    鈴木 直輝, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 井泉 瑠美子, 割田 仁, 浅田 隆太, 西野 一三, 青木 正志

    日本筋学会学術集会・筋ジストロフィー医療研究会合同学術集会プログラム・抄録集　9回・10回　63-63　2023/08

    Publisher: 日本筋学会・筋ジストロフィー医療研究会

  13. iPS細胞由来運動ニューロン軸索を用いた筋萎縮性側索硬化症の病態研究

    光澤志緒, 鈴木直輝, 青木正志

    日本解剖学会総会・全国学術集会抄録集(CD-ROM)　128th　2023

  14. 筋萎縮性側索硬化症では片側のみで正中神経刺激巨大体性感覚誘発電位を認めることがある

    板橋 泉, 浅黄 優, 四條 友望, 鈴木 直輝, 坂本 美佳, 佐藤 貴文, 小澤 鹿子, 青木 正志, 三木 俊, 中里 信和

    臨床神経生理学　50　(5)　400-400　2022/10

    Publisher: (一社)日本臨床神経生理学会

    ISSN： 1345-7101

    eISSN： 2188-031X

  15. 【炎症性筋疾患に関する最新の知見】封入体筋炎

    井泉 瑠美子, 鈴木 直輝, 青木 正志

    臨床免疫・アレルギー科　78　(4)　430-437　2022/10

    Publisher: (有)科学評論社

    ISSN： 1881-1930

  16. 大規模レジストリデータベースを活用したALS治験(ROPALS試験)におけるロピニロール塩酸塩の有効性の検証

    高橋 愼一, 森本 悟, 伊東 大介, 伊達 悠岳, 岡田 健佑, Chyi Muh Chai, 西山 亜由美, 鈴木 直輝, 平井 美和, 加部 泰明, 末松 誠, 陣崎 雅弘, 青木 正志, 佐藤 泰憲, 中原 仁, 鈴木 則宏, 岡野 栄之

    脳循環代謝　34　(1)　142-142　2022/10

    Publisher: (一社)日本脳循環代謝学会

    ISSN： 0915-9401

    eISSN： 2188-7519

  17. 分子病態に根差した炎症性筋疾患の治療開発アップデート 封入体筋炎の病態の理解と治療開発

    鈴木 直輝

    日本筋学会学術集会プログラム・抄録集　8回　24-24　2022/08

    Publisher: (一社)日本筋学会

    ISSN： 2433-975X

  18. アミノペプチダーゼによる筋分化制御メカニズムの解明

    長名 シオン, 北嶋 康雄, 鈴木 直輝, 高田 拓明, 村山 和隆, 永富 良一

    日本筋学会学術集会プログラム・抄録集　8回　144-144　2022/08

    Publisher: (一社)日本筋学会

    ISSN： 2433-975X

  19. 高度の嚥下障害と認知機能低下を認めた若年発症眼咽頭型筋ジストロフィーの1例

    大野 尭之, 井泉 瑠美子, 鈴木 直輝, 高井 良樹, 小野 理佐子, 黒田 宙, 割田 仁, 竪山 真規, 川崎 永美子, 鈴木 靖士, 青木 正志

    臨床神経学　62　(5)　409-409　2022/05

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  20. 若手研究者による骨格筋の分子生物学-基礎から臨床まで- 細胞膜修復異常と異常蛋白凝集を呈する筋疾患の病態・治療研究

    鈴木 直輝

    体力科学　71　(1)　55-55　2022/02

    Publisher: (一社)日本体力医学会

    ISSN： 0039-906X

    eISSN： 1881-4751

  21. 筋萎縮性側索硬化症では片側のみで正中神経刺激巨大体性感覚誘発電位を認めることがある

    板橋泉, 浅黄優, 四條友望, 鈴木直輝, 坂本美佳, 佐藤貴文, 小澤鹿子, 青木正志, 三木俊, 中里信和

    臨床神経生理学(Web)　50　(5)　2022

    ISSN： 2188-031X

  22. 大規模レジストリデータベースを活用したALS治験(ROPALS試験)におけるロピニロール塩酸塩の有効性の検証

    高橋愼一, 高橋愼一, 高橋愼一, 森本悟, 森本悟, 伊東大介, 伊東大介, 伊達悠岳, 岡田健佑, CHAI Muh Chyi, CHAI Muh Chyi, 西山亜由美, 鈴木直輝, 平井美和, 加部泰明, 末松誠, 陣崎雅弘, 青木正志, 佐藤泰憲, 中原仁, 鈴木則宏, 岡野栄之

    脳循環代謝(Web)　34　(1)　2022

    ISSN： 2188-7519

  23. PNPLA2遺伝子新規変異を伴った中性脂肪蓄積症ミオパチー/中性脂肪蓄積心筋血管症の1例

    坂田 花美, 森川 みゆき, 中村 尚子, 寒川 真, 平野 牧人, 西野 一三, 井泉 瑠美子, 鈴木 直輝, 黒田 宙, 滋賀 健介, 青木 正志, 楠 進

    臨床神経学　62　(1)　55-55　2022/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  24. 日本人一般集団に高頻度で見出され病的バリアントであると判断しがたいジスフェルリン遺伝子のc.3725G>A(p.R1242H)の神経筋疾患での頻度

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 小野 洋也, 戸恒 智子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究　8　41-41　2021/11

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  25. 【筋疾患診療の進歩】遠位型ミオパチーのシアル酸治療

    青木 正志, 井泉 瑠美子, 鈴木 直輝

    BIO Clinica　36　(9)　838-842　2021/08

    Publisher: (株)北隆館

    ISSN： 0919-8237

  26. 両側小脳病変を呈し、MELASが疑われた兄妹例

    船山 由希乃, 原田 龍平, 鈴木 直輝, 三須 建郎, 青木 正志

    臨床神経学　61　(7)　509-509　2021/07

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  27. Results Of A Randomized Clinical Trial of Ropinirole Hydrochloride For ALS (ROPALS)

    高橋愼一, 高橋愼一, 高橋愼一, 森本悟, 森本悟, 伊東大介, 伊達悠岳, 岡田健佑, CHAI Muh Chyi, 西山亜由美, 鈴木直輝, 平井美和, 加部泰明, 末松誠, 陣崎雅弘, 青木正志, 佐藤泰憲, 中原仁, 鈴木則宏, 岡野栄之

    脳循環代謝(Web)　33　(1)　2021

    ISSN： 2188-7519

  28. 多系統蛋白質症(MSP)患者の全国実態調査と診療体制構築に関する研究 HNRNPA1変異を伴う多系統蛋白質症(MSP3型)新規家系の同定

    青木正志, 割田仁, 井泉瑠美子, 井泉瑠美子, 池田謙輔, 鈴木直輝, 高橋俊明, 竪山真規, 西山亜由美, 城田松之, 舟山亮, 中山啓子, 三橋里美, 西野一三, 新堀哲也, 青木洋子

    多系統蛋白質症(MSP)患者の全国実態調査と診療体制構築に関する研究 令和2年度 総括・分担研究報告書(Web)　2021

  29. iPS細胞創薬に基づいた筋萎縮性側索硬化症(ALS)に対するロピニロール塩酸塩の医師主導治験(ROPALS試験)

    森本悟, 森本悟, 高橋愼一, 高橋愼一, 高橋愼一, 伊東大介, 伊達悠岳, 岡田健佑, CHAI Muh Chyi, CHAI Muh Chyi, 西山亜由美, 鈴木直輝, 平井美和, 加部泰明, 末松誠, 陣崎雅弘, 青木正志, 佐藤泰憲, 中原仁, 鈴木則宏, 岡野栄之

    神経治療学(Web)　38　(6)　2021

    ISSN： 2189-7824

  30. 日本人一般集団に高頻度で見出されるジスフェルリン遺伝子のc.3725G>A(p.R1242H)バリアントの臨床像の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 戸恒 智子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    筋ジストロフィー医療研究　7　65-65　2021/01

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  31. 封入体筋炎に対するHAL治療の有効性について

    鈴木 直輝, 曽我 天馬, 井泉 瑠美子, 豊嶋 昌弥, 芝崎 美和子, 佐藤 いつみ, 工藤 悠, 青木 正志, 加藤 昌昭

    日本筋学会学術集会プログラム・抄録集　6回　124-124　2020/12

    Publisher: 日本筋学会

    ISSN： 2433-975X

  32. 前臨床に有用なALSモデルを考える ALSのiPS細胞モデルの有用性と特性

    鈴木 直輝

    臨床神経学　60　(Suppl.)　S55-S55　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  33. 知っておきたい!進化する難治性筋疾患の新展開 封入体筋炎の診断と新たな治療に向けて

    青木 正志, 鈴木 直輝, 井泉 瑠美子, 割田 仁, 森 まどか, 山下 賢, 橋口 昭大, 梶 龍兒, 村田 顕也, 杉江 和馬, 西野 一三

    臨床神経学　60　(Suppl.)　S90-S90　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  34. まるごと2時間封入体筋炎〜up to dateとpitfall〜 高齢化社会で重要性を増す封入体筋炎:疫学データを中心に

    青木 正志, 井泉 瑠美子, 鈴木 直輝

    臨床神経学　60　(Suppl.)　S128-S128　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  35. 入院終末期対応を行ったALSの現状と問題点について

    加藤 昌昭, 鈴木 直輝, 井泉 瑠美子, 曽我 天馬, 川内 裕子, 青木 正志

    臨床神経学　60　(Suppl.)　S325-S325　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  36. 日本におけるSOD1遺伝子変異陽性筋萎縮性側索硬化症患者の臨床的特徴

    中村 亮一, 熱田 直樹, 藤内 玄規, 林 直毅, 勝野 雅央, 和泉 唯信, 金井 数明, 服部 信孝, 谷口 彰, 森田 光哉, 狩野 修, 澁谷 和幹, 桑原 聡, 鈴木 直輝, 青木 正志, 阿部 康二, 石原 智彦, 小野寺 理, 梶 龍兒, 祖父江 元

    臨床神経学　60　(Suppl.)　S381-S381　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  37. 多施設共同前向きコホートでみたALS患者の非侵襲的人工換気療法に関する予後の検討

    林 直毅, 熱田 直樹, 横井 大知, 中村 亮一, 勝野 雅央, 和泉 唯信, 金井 数明, 服部 信孝, 谷口 彰, 森田 光哉, 狩野 修, 澁谷 和幹, 桑原 聡, 鈴木 直輝, 青木 正志, 織田 雅也, 饗場 郁子, 梶 龍兒, 祖父江 元

    臨床神経学　60　(Suppl.)　S381-S381　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  38. 日本人一般集団に高頻度で見出されるdysferlin遺伝子のc.3725G>A(p.R1242H)の検討

    高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 島倉 奈緒子, 大矢 寧, 佐橋 功, 小野 洋也, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　60　(Suppl.)　S387-S387　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  39. ジスフェルリン異常症209家系の臨床遺伝学的特徴

    井泉 瑠美子, 高橋 俊明, 鈴木 直輝, 新堀 哲也, 小野 洋也, 中村 尚子, 堅田 慎一, 加藤 昌昭, 割田 仁, 竪山 真規, 青木 洋子, 青木 正志

    臨床神経学　60　(Suppl.)　S387-S387　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  40. PNPLA2遺伝子関連中性脂肪蓄積病の臨床像

    寒川 真, 中村 尚子, 平野 牧人, 森川 みゆき, 坂田 花美, 西野 一三, 井泉 瑠美子, 鈴木 直輝, 黒田 宙, 滋賀 健介, 青木 正志, 楠 進

    臨床神経学　60　(Suppl.)　S388-S388　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  41. 封入体筋炎に対するHAL治療の有効性について

    鈴木 直輝, 芝崎 美和子, 佐藤 いつみ, 工藤 悠, 曽我 天馬, 井泉 瑠美子, 青木 正志, 加藤 昌昭

    臨床神経学　60　(Suppl.)　S395-S395　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  42. 在宅侵襲的人工呼吸器装着筋萎縮性側索硬化症患者の施設間情報共有の試み

    松本 有史, 石橋 渚子, 関本 聖子, 遠藤 久美子, 鈴木 直輝, 加藤 昌昭, 青木 正志, 永野 功

    臨床神経学　60　(Suppl.)　S408-S408　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  43. 当院におけるALS患者に対する誤嚥防止術5例の長期経過

    曽我 天馬, 井泉 瑠美子, 鈴木 直輝, 川内 裕子, 加藤 健吾, 香取 幸夫, 青木 正志, 加藤 昌昭

    臨床神経学　60　(Suppl.)　S450-S450　2020/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  44. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学　37　(6)　S101-S101　2020/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  45. 遺伝性筋疾患におけるトランスレーショナル・リサーチ GNEミオパチーの治療法開発

    青木 正志, 鈴木 直輝, 井泉 瑠美子, 割田 仁, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 西野 一三

    神経治療学　37　(4)　656-660　2020/07

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  46. Inhibition of leucine aminopeptidase affects myocyte proliferation and differentiation

    Shion Osana, Kazutaka Murayama, Naoki Suzuki, Hiroaki Takada, Takahiro Kubota, Ryoichi Nagatomi

    FASEB JOURNAL　34　2020/04

    DOI： 10.1096/fasebj.2020.34.s1.02075 　

    ISSN： 0892-6638

    eISSN： 1530-6860

  47. 【筋炎の診断と治療の新たな展開】増えてきた封入体筋炎

    鈴木 直輝, 井泉 瑠美子, 青木 正志

    神経治療学　37　(2)　135-140　2020/03

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  48. Inclusion body myositis-an increasing entity

    鈴木直輝, 井泉瑠美子, 青木正志

    神経治療学(Web)　37　(2)　2020

    ISSN： 2189-7824

  49. 封入体筋炎患者を対象とするBYM338の後期第II相/第III相試験(RESILIENT) 日本人部分集団データ

    森 まどか, 山下 賢, 鈴木 直輝, 勝野 雅央, 村田 顕也, 野寺 裕之, 手島 梨恵, 稲村 達海, 西野 一三, 青木 正志

    臨床神経学　59　(12)　806-813　2019/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  50. 日本人dysferlin遺伝子解析で見出されたバリアントの一般頻度による病的意義の推定

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 杉村 容子, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    臨床神経学　59　(Suppl.)　S257-S257　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  51. PM-Mito様筋病理を呈した抗PM/Scl抗体陽性炎症性筋疾患の1例

    松本 有史, 井泉 瑠美子, 菅野 直人, 鈴木 直輝, 永野 功

    臨床神経学　59　(Suppl.)　S310-S310　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  52. MCTDに伴う筋炎10例の臨床病理学的検討

    阪本 直広, 井泉 瑠美子, 鈴木 直輝, 竪山 真規, 青木 正志

    臨床神経学　59　(Suppl.)　S338-S338　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  53. 多施設共同前向きコホートでみたALS患者の背景と予後因子の検討

    林 直毅, 熱田 直樹, 横井 大知, 中村 亮一, 勝野 雅央, 和泉 唯信, 金井 数明, 服部 信孝, 谷口 彰, 森田 光哉, 狩野 修, 澁谷 和幹, 桑原 聡, 鈴木 直輝, 青木 正志, 餐場 育子, 溝口 功一, 梶 龍兒, 祖父江 元, JaCALS

    臨床神経学　59　(Suppl.)　S359-S359　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  54. 侵襲的人工呼吸器装着ALS患者の定期的評価入院における身体機能評価表の作成および運用の試み

    石橋 渚子, 関本 聖子, 遠藤 久美子, 山内 悦子, 川内 裕子, 松本 有史, 鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    日本難病医療ネットワーク学会機関誌　7　(1)　84-84　2019/11

    Publisher: 日本難病医療ネットワーク学会

    ISSN： 2188-1006

  55. 【ALS 2019】家族性ALS

    鈴木 直輝, 西山 亜由美, 加藤 昌昭, 割田 仁, 青木 正志

    BRAIN and NERVE: 神経研究の進歩　71　(11)　1169-1181　2019/11

    Publisher: (株)医学書院

    ISSN： 1881-6096

    eISSN： 1344-8129

  56. 【ALS 2019】HGFによる治療法開発

    青木 正志, 割田 仁, 加藤 昌昭, 鈴木 直輝

    BRAIN and NERVE: 神経研究の進歩　71　(11)　1253-1260　2019/11

    Publisher: (株)医学書院

    ISSN： 1881-6096

    eISSN： 1344-8129

  57. 頭部外傷を契機に発症した抗MOG抗体関連脳脊髄炎の一例

    佐藤 一輝, 西山 亜由美, 鈴木 直輝, 張替 宗介, 齋藤 早紀, 池田 謙輔, 西山 修平, 三須 建郎, 割田 仁, 黒田 宙, 青木 正志

    臨床神経学　59　(11)　760-760　2019/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  58. 遺伝性筋疾患におけるトランスレーショナル・リサーチ GNEミオパチーの治療法開発

    青木 正志, 鈴木 直輝, 割田 仁, 森 まどか, 勝野 雅央, 高橋 正紀, 山下 賢, 西野 一三

    神経治療学　36　(6)　S163-S163　2019/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  59. ユビキチン-プロテアソーム系は筋幹細胞の恒常性維持に必須である

    北嶋 康雄, 鈴木 直輝, 布宮 亜樹, 長名 シオン, 吉岡 潔志, 田代 善崇, 高橋 良輔, 小野 悠介, 青木 正志, 永富 良一

    日本筋学会学術集会プログラム・抄録集　5回　131-131　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  60. ユビキチン-プロテアソーム系は筋幹細胞の恒常性維持に必須である

    北嶋 康雄, 鈴木 直輝, 布宮 亜樹, 長名 シオン, 吉岡 潔志, 田代 善崇, 高橋 良輔, 小野 悠介, 青木 正志, 永富 良一

    日本筋学会学術集会プログラム・抄録集　5回　131-131　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  61. 日本人dysferlin遺伝子解析で見出されたバリアントのデータベースによる検討

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 割田 仁, 新堀 哲也, 武田 篤, 青木 洋子, 青木 正志

    日本筋学会学術集会プログラム・抄録集　5回　172-172　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  62. 封入体筋炎の患者アンケート調査

    鈴木 直輝, 森 まどか, 山下 賢, 木村 円, 竪山 真規, 井泉 瑠美子, 小野 洋也, 高橋 俊明, 西野 一三, 青木 正志

    日本筋学会学術集会プログラム・抄録集　5回　191-191　2019/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  63. 脳生検により炎症性脱髄性疾患である可能性が示唆された嗜眠性脳炎の1例

    大野 尭之, 高井 良樹, 鈴木 直輝, 菅野 直人, 小野 理佐子, 黒田 宙, 勝木 将人, 西嶌 泰生, 新妻 邦泰, 渡辺 みか, 神林 崇, 青木 正志

    臨床神経学　59　(7)　477-477　2019/07

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  64. 炎症性筋疾患におけるミトコンドリア機能異常の検討とその治療法開発

    及川善嗣, 井泉瑠美子, 小出将志, 萩原嘉廣, 神崎展, 鈴木直輝, 青木正志, 阿部高明, 阿部高明, 阿部高明

    日本NO学会学術集会プログラム抄録集　19th　67　2019/06/01

  65. 【指定難病ペディア2019】個別の指定難病 神経・筋系 封入体筋炎[指定難病15]

    鈴木 直輝, 青木 正志

    日本医師会雑誌　148　(特別1)　S100-S101　2019/06

    Publisher: (公社)日本医師会

    ISSN： 0021-4493

  66. ユビキチン-プロテアソーム系は筋幹細胞の恒常性維持に必須である

    北嶋 康雄, 鈴木 直輝, 布宮 亜樹, 長名 シオン, 吉岡 潔志, 田代 善崇, 高橋 良輔, 小野 悠介, 青木 正志, 永富 良一

    基礎老化研究　43　(2)　88-88　2019/06

    Publisher: 日本基礎老化学会

    ISSN： 0912-8921

  67. 【運動ニューロン疾患-治療の展望】筋萎縮性側索硬化症のHGFによる治療開発

    青木 正志, 割田 仁, 鈴木 直輝, 加藤 昌昭

    脳神経内科　90　(2)　146-153　2019/02

    Publisher: (有)科学評論社

    ISSN： 2434-3285

  68. 脳生検により炎症性脱髄性疾患である可能性が示唆された嗜眠性脳炎の1例

    大野尭之, 高井良樹, 鈴木直輝, 菅野直人, 小野理佐子, 黒田宙, 勝木将人, 西嶌泰生, 新妻邦泰, 渡辺みか, 神林崇, 青木正志

    臨床神経学(Web)　59　(7)　2019

    ISSN： 1882-0654

  69. Therapeutic development of amyotrophic lateral sclerosis based on rodent model

    鈴木直輝, 青木正志

    神経治療学(Web)　35　(4)　488‐493(J‐STAGE)　2019

    DOI： 10.15082/jsnt.35.4_488 　

    ISSN： 2189-7824

  70. 過敏性腸症候群とグルココルチコイド受容体遺伝子多型との関連について

    佐々木 彩加, 小室 葉月, 鈴木 直輝, 佐藤 菜保子, 鹿野 理子, 金澤 素, 青木 正志, 福土 審

    心身医学　59　(1)　79-80　2019/01

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  71. 日本人に見出されたdysferlin遺伝子のバリアントの病的意義の検討

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    臨床神経学　58　(Suppl.)　S212-S212　2018/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  72. リルゾール投与中止に至った筋萎縮性側索硬化症(ALS)複数例の検討

    澁井 彩, 加藤 昌昭, 鈴木 直輝, 井泉 瑠美子, 川内 裕子, 割田 仁, 青木 正志

    臨床神経学　58　(Suppl.)　S319-S319　2018/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  73. 肢帯型筋ジストロフィー2B型患者の脳画像所見

    小原 講二, 畠山 知之, 阿部 エリカ, 小林 道雄, 和田 千鶴, 豊島 至, 間宮 繁夫, 高橋 俊明, 井泉 瑠美子, 鈴木 直輝, 青木 正志

    あきた病院医学雑誌　7　(1)　51-53　2018/12

    Publisher: (独)国立病院機構あきた病院

    ISSN： 2187-5421

  74. 日本人に見出されたdysferlin遺伝子のバリアントの病的意義の検討

    高橋俊明, 鈴木直輝, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 杉村容子, 谷口さやか, 下瀬川康子, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    日本神経学会学術大会プログラム・抄録集　58　(Suppl.)　S212-S212　2018/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  75. リルゾール投与中止に至った筋萎縮性側索硬化症(ALS)複数例の検討

    澁井彩, 加藤昌昭, 鈴木直輝, 井泉瑠美子, 川内裕子, 割田仁, 青木正志

    日本神経学会学術大会プログラム・抄録集　58　(Suppl.)　S319-S319　2018/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  76. 【ミオパチー-最近の話題-】GNEミオパチーに対するシアル酸療法

    井泉 瑠美子, 鈴木 直輝, 青木 正志

    神経内科　89　(5)　481-488　2018/11

    Publisher: (有)科学評論社

    ISSN： 0386-9709

  77. 肢帯型筋ジストロフィー2B型(dysferlinopathy)患者の脳画像所見の検討

    小原 講二, 阿部 エリカ, 小林 道雄, 和田 千鶴, 間宮 繁夫, 豊島 至, 高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 青木 正志, 畠山 知之

    国立病院総合医学会講演抄録集　72回　736-736　2018/11

    Publisher: 国立病院総合医学会

  78. 日本人dysferlin遺伝子解析で見出された全バリアントの検討

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 倉島 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 洋子, 青木 正志

    国立病院総合医学会講演抄録集　72回　737-737　2018/11

    Publisher: 国立病院総合医学会

  79. 人工呼吸器装着ALSにおける誤嚥防止術と持続吸引使用の検討

    加藤 昌昭, 川内 裕子, 鈴木 直輝, 加藤 建吾, 青木 正志

    神経治療学　35　(6)　S230-S230　2018/11

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  80. コルチコトロピン放出ホルモン受容体2(CRHR2)遺伝子における一塩基多型と過敏性腸症候群との関連

    小室 葉月, 佐藤 菜保子, 佐々木 彩加, 鈴木 直輝, 金澤 素, 青木 正志, 福土 審

    心身医学　58　(7)　645-645　2018/10

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  81. 骨格筋mRNAのスプライス異常を確認できたイントロンのジスフェルリン遺伝子変異

    高橋 俊明, 小野 洋也, 八木沼 智香子, 中西 浩隆, 久留 聡, 島倉 奈緒子, 井泉 瑠美子, 鈴木 直輝, 下瀬川 康子, 大城 咲, 杉村 容子, 谷口 さやか, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    筋ジストロフィー医療研究　5　103-103　2018/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  82. コルチコトロピン放出ホルモン受容体2(CRHR2)遺伝子における一塩基多型と過敏性腸症候群との関連

    小室 葉月, 佐藤 菜保子, 佐々木 彩加, 鈴木 直輝, 金澤 素, 青木 正志, 福土 審

    心身医学　58　(7)　645-645　2018/10

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  83. 【神経疾患治療の進歩 2017】運動ニューロン疾患の治療の進歩

    秋山 徹也, 鈴木 直輝, 割田 仁, 青木 正志

    神経治療学　35　(5)　609-613　2018/09

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  84. 骨格筋幹細胞におけるプロテアソームの役割解明

    北嶋 康雄, 鈴木 直輝, 布宮 亜樹, 長名 シオン, 田代 善崇, 高橋 良輔, 小野 悠介, 青木 正志, 永富 良一

    日本筋学会学術集会プログラム・抄録集　4回　125-125　2018/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  85. 骨格筋特異的PHD2欠損が持久性トレーニング効果に与える影響

    布宮 亜樹, 長名 シオン, 高田 拓明, 北嶋 康雄, 鈴木 直輝, 青木 正志, 段 孝, 宮田 敏男, 永富 良一

    日本筋学会学術集会プログラム・抄録集　4回　134-134　2018/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  86. 細胞膜修復機構に着目したdysferlin異常症の病態解明と治療法開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　4回　160-160　2018/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  87. 日本人に見出されたdysferlin遺伝子のコード上ストップコドンの出現しないSNPsの病的意義の検討

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 大城 咲, 谷口 さやか, 下瀬川 康子, 馬場 徹, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    日本筋学会学術集会プログラム・抄録集　4回　190-190　2018/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  88. 次世代シークエンサーを用いたジスフェルリン異常症の遺伝子解析

    井泉 瑠美子, 新堀 哲也, 高橋 俊明, 鈴木 直輝, 竪山 真規, 小野 洋也, 加藤 昌昭, 割田 仁, 青木 洋子, 青木 正志

    日本筋学会学術集会プログラム・抄録集　4回　191-191　2018/08

    Publisher: 日本筋学会

    ISSN： 2433-975X

  89. 次世代シークエンサーで診断された肢体型筋ジストロフィー2B型の一例

    中山 湧貴, 加藤 量広, 成川 孝一, 及川 崇紀, 井泉 瑠美子, 鈴木 直輝, 青木 正志, 高橋 俊明

    臨床神経学　58　(8)　537-537　2018/08

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  90. 細胞膜修復機構に着目したdysferlin異常症の病態解明と治療法開発

    小野洋也, 小野洋也, 鈴木直輝, 菅野新一郎, 川原玄理, 井泉瑠美子, 高橋俊明, 北嶋康雄, 長名シオン, 秋山徹也, 池田謙輔, 四條友望, 光澤志緒, 割田仁, 永富良一, 荒木伸一, 安井明, 林由起子, 三宅克也, 三宅克也, 青木正志

    日本筋学会学術集会プログラム・抄録集　4th　160-160　2018/08/01

    Publisher: 日本筋学会

    ISSN： 2433-975X

  91. 次世代シークエンサーを用いたジスフェルリン異常症の遺伝子解析

    井泉瑠美子, 新堀哲也, 高橋俊明, 鈴木直輝, 竪山真規, 小野洋也, 加藤昌昭, 割田仁, 青木洋子, 青木正志

    日本筋学会学術集会プログラム・抄録集　4th　191-191　2018/08/01

    Publisher: 日本筋学会

    ISSN： 2433-975X

  92. 日本人に見出されたdysferlin遺伝子のコード上ストップコドンの出現しないSNPsの病的意義の検討

    高橋俊明, 鈴木直輝, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 大城咲, 谷口さやか, 下瀬川康子, 馬場徹, 大泉英樹, 田中洋康, 吉岡勝, 武田篤, 青木正志

    日本筋学会学術集会プログラム・抄録集　4th　190-190　2018/08/01

    Publisher: 日本筋学会

    ISSN： 2433-975X

  93. 骨格筋特異的PHD2欠損が持久性トレーニング効果に与える影響

    布宮亜樹, 長名シオン, 高田拓明, 北嶋康雄, 鈴木直輝, 青木正志, 段孝, 宮田敏男, 永富良一

    日本筋学会学術集会プログラム・抄録集　4th　134-134　2018/08/01

    Publisher: 日本筋学会

    ISSN： 2433-975X

  94. 骨格筋幹細胞におけるプロテアソームの役割解明

    北嶋康雄, 北嶋康雄, 鈴木直輝, 布宮亜樹, 長名シオン, 田代善崇, 高橋良輔, 小野悠介, 青木正志, 永富良一

    日本筋学会学術集会プログラム・抄録集　4th　125-125　2018/08/01

    Publisher: 日本筋学会

    ISSN： 2433-975X

  95. 運動ニューロン疾患 治療の展望 齧歯類モデルを基盤とした筋萎縮性側索硬化症の治療開発

    鈴木 直輝, 青木 正志

    神経治療学　35　(4)　488-493　2018/07

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  96. 呼吸としゃっくり 呼吸障害とその治療 筋萎縮性側索硬化症

    鈴木直輝, 加藤昌昭, 青木正志

    Clinical Neuroscience　36　(7)　834-837　2018/07

    Publisher: (株)中外医学社

    ISSN： 0289-0585

  97. 長期経過中に敗血症で死亡した家族性広汎型筋萎縮性側索硬化症の一剖検例

    宮代 麻由, 鬼塚 裕美, 武田 貴裕, 山本 智子, 鈴木 直輝, 西山 亜由美, 青木 正志, 北川 一夫, 柴田 亮行

    日本病理学会会誌　107　(1)　532-532　2018/04

    Publisher: (一社)日本病理学会

    ISSN： 0300-9181

  98. 長期経過中に敗血症で死亡した家族性広汎型筋萎縮性側索硬化症の一剖検例

    宮代 麻由, 鬼塚 裕美, 武田 貴裕, 山本 智子, 鈴木 直輝, 西山 亜由美, 青木 正志, 北川 一夫, 柴田 亮行

    日本病理学会会誌　107　(1)　532-532　2018/04

    Publisher: (一社)日本病理学会

    ISSN： 0300-9181

  99. 縁取り空胞を伴う遠位型(GNE)ミオパチーに対するシアル酸治療の開発

    鈴木直輝, 青木正志

    月刊難病と在宅ケア　24　(1)　28-30　2018/04

    Publisher: (株)日本プランニングセンター

    ISSN： 1880-9200

  100. 臨床研究を指向したナショナルレジストリーと指定難病登録のあり方に関する研究

    木村円, 木村円, 森まどか, 高橋正紀, 石山昭彦, 山下賢, 南成祐, 鈴木直輝, 齊藤利雄, 中村治雅, 中村治雅, 小牧宏文, 小牧宏文, 西野一三, 青木正志

    筋ジストロフィーの標準的医療普及のための調査研究 平成29年度 総括・分担研究報告書(Web)　2018

  101. Review/Advances in Neurological Therapeutics (2016). Motor neuron disease

    鈴木直輝, 加藤昌昭, 割田仁, 青木正志

    神経治療学(Web)　34　(5)　518‐522(J‐STAGE)　2018

    DOI： 10.15082/jsnt.34.5_518 　

    ISSN： 2189-7824

  102. 日本人dysferlin遺伝子の意義の確定できないSNPs

    高橋 俊明, 鈴木 直輝, 井泉 瑠美子, 八木沼 智香子, 小野 洋也, 島倉 奈緒子, 杉村 容子, 谷口 さやか, 下瀬川 康子, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    国立病院総合医学会講演抄録集　71回　1126-1126　2017/11

    Publisher: 国立病院総合医学会

  103. 運動ニューロン疾患:治療の展望 齧歯類モデルを基盤としたALSの治療開発 HGFを中心に

    鈴木 直輝

    神経治療学　34　(6)　S118-S118　2017/11

    Publisher: 日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  104. 筋ジストロフィー治療研究の最前線

    青木 正志, 井泉 瑠美子, 高橋 俊明, 小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 北嶋 康雄, 長名 シオン, 秋山 哲也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 武田 篤

    筋ジストロフィー医療研究　4　18-18　2017/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  105. 細胞膜修復機構に着目したジスフェルリン異常症の病態解明と治療法開発

    小野洋也, 鈴木直輝, 菅野新一郎, 川原玄理, 井泉瑠美子, 高橋俊明, 北嶋康雄, 長名シオン, 秋山徹也, 池田謙輔, 四條友望, 光澤志緒, 割田仁, 永富良一, 荒木伸一, 安井明, 林由起子, 三宅克也, 三宅克也, 青木正志

    筋ジストロフィー医療研究　4　87-87　2017/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  106. 封入体筋炎の実態調査アンケート結果

    鈴木直輝, 森まどか, 山下賢, 中野智, 村田顕也, 稲森由紀恵, 松井尚子, 木村円, 日下博文, 近藤智善, 樋口逸郎, 梶龍兒, 竪山真規, 井泉瑠美子, 小野洋也, 加藤昌昭, 割田仁, 高橋俊明, 西野一三, 武田篤, 青木正志

    筋ジストロフィー医療研究　4　117-117　2017/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  107. 日本人ジスフェルリン異常症で最も高頻度で,肢帯型と関連し軽症となるp.Trp999Cysと予想されるc.2997G>T変異のスプライス異常の有無

    高橋俊明, 鈴木直輝, 小野洋也, 中西浩隆, 久留聡, 島倉奈緒子, 八木沼智香子, 井泉瑠美子, 下瀬川康子, 杉村容子, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    筋ジストロフィー医療研究　4　85-85　2017/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  108. 次世代シークエンサーを用いたジスフェルリン異常症の遺伝子解析

    井泉瑠美子, 新堀哲也, 高橋俊明, 八木沼智香子, 鈴木直輝, 島倉奈緒子, 竪山真規, 竪山真規, 小野洋也, 加藤昌昭, 割田仁, 武田篤, 青木洋子, 青木正志

    筋ジストロフィー医療研究　4　86-86　2017/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  109. 【神経疾患治療の進歩2016】運動ニューロン疾患の治療の進歩

    鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    神経治療学　34　(5)　518-522　2017/09

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  110. 細胞膜修復機構に着目したDysferlinopathyの病態解明と治療法開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　3回　141-141　2017/07

    Publisher: 日本筋学会

    ISSN： 2433-975X

  111. GNEミオパチーに対するシアル酸補充による医師主導治験

    鈴木直輝

    日本筋学会学術集会プログラム・抄録集　3回　64-64　2017/07

    Publisher: 日本筋学会

    ISSN： 2433-975X

  112. 細胞膜修復機構に着目したDysferlinopathyの病態解明と治療法開発

    小野洋也, 鈴木直輝, 菅野新一郎, 川原玄理, 井泉瑠美子, 高橋俊明, 北嶋康雄, 長名シオン, 秋山徹也, 池田謙輔, 四條友望, 光澤志緒, 割田仁, 永富良一, 荒木伸一, 安井明, 林由起子, 三宅克也, 三宅克也, 青木正志

    日本筋学会学術集会プログラム・抄録集　3回　141-141　2017/07

    Publisher: 日本筋学会

    ISSN： 2433-975X

  113. 脊椎・脊髄疾患と筋萎縮 神経変性疾患による筋萎縮

    鈴木直輝, 青木正志

    脊椎脊髄ジャーナル　30　(5)　557‐562　2017/05/25

    DOI： 10.11477/mf.5002200635 　

    ISSN： 0914-4412

  114. マイクロ流体デバイスを用いた運動ニューロンの軸索病態の解析

    鈴木直輝, 秋山徹也, 川田治良, 川田治良, 舟山亮, 岡野栄之, 中山啓子, 藤井輝夫, 青木正志

    日本細胞生物学会大会(Web)　69回　25-25　2017/05

    Publisher: (一社)日本細胞生物学会

  115. Hypoxic response in skeletal muscle contributes to the adaptation of muscle fibers in mice

    Aki Nunomiya, Junchul Shin, Yasuo Kitajima, Takashi Dan, Toshio Miyata, Naoki Suzuki, Masashi Aoki, Ryoichi Nagatomi

    FASEB JOURNAL　31　2017/04

    ISSN： 0892-6638

    eISSN： 1530-6860

  116. The detection of the proteasomal proteolysis efficiency in C2C12 myoblast Peer-reviewed

    Shion Osana, Naoki Suzuki, Masashi Aoki, Ryoichi Nagatomi

    FASEB JOURNAL　31　(1)　2017/04

    ISSN： 0892-6638

    eISSN： 1530-6860

  117. 筋肉研究の最前線 縁取り空胞を伴う遠位型(GNE)ミオパチーの治療開発

    鈴木直輝, 井泉瑠美子, 加藤昌昭, 割田仁, 青木正志

    Clinical Calcium　27　(3)　429‐434　2017/02/28

    ISSN： 0917-5857

  118. 筋萎縮性側索硬化症ラットモデル脊髄における内在性再生機転

    割田仁, 四條友望, 池田謙輔, 小野洋也, 秋山徹也, 光澤志緒, 西山亜由美, 井泉瑠美子, 鈴木直輝, 青木正志

    再生医療　16　436　2017/02/01

    ISSN： 1347-7919

  119. 筋萎縮性側索硬化症モデルラットにおけるコンドロイチン硫酸プロテオグリカン受容体の異所性発現

    四條友望, 割田仁, 鈴木直輝, 池田謙輔, 秋山徹也, 小野洋也, 光澤志緒, 西山亜由美, 井泉瑠美子, 青木正志

    再生医療　16　435　2017/02/01

    ISSN： 1347-7919

  120. Science Translational Medicineに載った日本人2016

    鈴木 直輝

    2017

  121. 運動ニューロン疾患の治療の進歩

    鈴木直輝, 加藤昌昭, 割田仁, 青木正志

    神経治療学(Web)　33　(4)　529‐532(J‐STAGE)-532　2017

    Publisher: Japanese Society of Neurological Therapeutics

    DOI： 10.15082/jsnt.33.4_529 　

    ISSN： 2189-7824

    More details Close

    <p>Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. Only supportive care and riluzole are available worldwide to date. This review provides a general overview of preclinical and clinical advances in 2015 and summarizes the literature regarding emerging therapeutic approaches. The topics include research using next–generation sequencing, progress in the pathomechanism of C9ORF72–mutated ALS, therapeutic strategies on mitochondrial pathology, novel investigation of therapies from Japan, strategies focusing on growth factors and neuro–inflammations, therapeutic strategies using iPS cells. We also discuss about the biomarkers and the problems of the design of clinical trials.</p>

  122. 筋ジストロフィー関連疾患の基盤的診断・治療開発研究 Dysferlinopathyおよび類似疾患の次世代シークエンサーを用いた診断および結合蛋白に注目した病態研究

    青木正志, 小野洋也, 井泉瑠美子, 鈴木直輝, 菅野新一郎, 高橋俊明, 割田仁, 加藤昌昭, 西山亜由美, 島倉奈緒子, 舟山亮, 中山啓子, 新堀哲也, 青木洋子, 三宅克也, 三宅克也

    筋ジストロフィー関連疾患の基盤的診断・治療開発研究 平成26-28年度 総括研究報告書　18‐20　2017

  123. 日本人dysferlin遺伝子の病的変異と確定できないSNPs

    高橋俊明, 鈴木直輝, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 杉村容子, 谷口さやか, 下瀬川康子, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　62nd　348　2017

  124. 難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 日本人ジスフェルリン異常症の遺伝子検索への次世代シークエンサーの導入

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 新堀哲也, 片山望, 齋藤京之, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木洋子, 三橋里美, 西野一三

    難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 平成28年度 総括・分担研究報告書(Web)　201610042A0007 (WEB ONLY)　2017

  125. 齧歯類モデルを基盤としたALSの治療開発:HGFを中心に

    鈴木直輝

    神経治療学(Web)　34　(6)　S118(J‐STAGE)　2017

    DOI： 10.15082/jsnt.34.6_S118 　

    ISSN： 2189-7824

  126. 遠位型ミオパチーに対するシアル酸治療

    青木正志, 鈴木直輝, 割田仁, 西野一三

    日本神経学会学術大会プログラム・抄録集　56　(Suppl.)　S41-S41　2016/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  127. 日本人dysferlinopathyで最も高頻度のc.2997G>T変異のスプライス異常の有無の検討

    高橋俊明, 鈴木直輝, 小野洋也, 中西浩隆, 久留聡, 島倉奈緒子, 八木沼智香子, 井泉瑠美子, 下瀬川康子, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    日本神経学会学術大会プログラム・抄録集　56　(Suppl.)　S280-S280　2016/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  128. 肝細胞増殖因子(HGF)を用いたALSの再生医療

    鈴木直輝

    臨床評価　44　(3)　611‐616　2016/12/01

    ISSN： 0300-3051

  129. 筋炎を初発症状とした筋外性NK/T細胞リンパ腫の1例

    川口 典彦, 小林 理子, 石垣 あや, 藤盛 寿一, 井泉 瑠美子, 鈴木 直輝, 竪山 真規, 青木 正志

    臨床神経学　56　(11)　808-808　2016/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  130. 原発性アミロイドーシスの1例

    斉藤 有佳, 菅野 重範, 宮澤 康一, 渋谷 聡, 下田 楓美子, 井泉 瑠美子, 鈴木 直輝, 堅山 真規

    臨床神経学　56　(11)　810-810　2016/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  131. 日本人dysferlinopathyで最も高頻度で軽症となりp.Trp999Cysと予想されるc.2997G>T変異の頻度とスプライス異常の有無

    高橋 俊明, 鈴木 直輝, 小野 洋也, 中西 浩隆, 久留 聡, 島倉 奈緒子, 八木沼 智香子, 井泉 瑠美子, 杉村 容子, 下瀬川 康子, 大泉 英樹, 田中 洋康, 吉岡 勝, 武田 篤, 青木 正志

    国立病院総合医学会講演抄録集　70回　O-1　2016/11

    Publisher: 国立病院総合医学会

  132. Proteasomal proteolysis is indispensable for the maintenance of skeletal muscle and muscle stem cells

    N. Suzuki, Y. Kitajima, Y. Tashiro, H. Ono, R. Ando, S. Osana, A. Nunomiya, R. Nagatomi, R. Takahashi, M. Aoki

    NEUROMUSCULAR DISORDERS　26　S94-S94　2016/10

    DOI： 10.1016/j.nmd.2016.06.035 　

    ISSN： 0960-8966

    eISSN： 1873-2364

  133. Research for the pathogenesis and therapy of dysferlinopathy using proteomics approach

    H. Ono, N. Suzuki, S. Kanno, K. Miyake, Y. Kitajima, R. Izumi, T. Takahashi, H. Warita, A. Yasui, M. Aoki

    NEUROMUSCULAR DISORDERS　26　S151-S152　2016/10

    DOI： 10.1016/j.nmd.2016.06.240 　

    ISSN： 0960-8966

    eISSN： 1873-2364

  134. 遺伝子治療可能な日本人dysferlinopathyの割合

    高橋俊明, 八木沼智香子, 鈴木直輝, 井泉瑠美子, 小野洋也, 杉村容子, 杉村容子, 島倉奈緒子, 谷口さやか, 下瀬川康子, 大泉英樹, 田中洋康, 吉岡勝, 武田篤, 青木正志

    筋ジストロフィー医療研究　3　91-91　2016/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  135. 認知症・神経変性疾患の克服への挑戦 III.新たな技術開発によるチャレンジ HGFによる筋萎縮性側索硬化症(ALS)に対する治療法の開発

    青木正志, 割田仁, 鈴木直輝, 加藤昌昭

    生体の科学　67　(4)　344‐348　2016/08/15

    DOI： 10.11477/mf.2425200466 　

    ISSN： 0370-9531

  136. 葉酸欠乏症の関与が疑われた脊髄長大病変の1例

    原田 龍平, 渡辺 源也, 高井 良樹, 鈴木 直輝, 黒田 宙, 割田 仁, 青木 正志

    臨床神経学　56　(8)　585-585　2016/08

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  137. 【神経疾患治療の進歩2015年】 運動ニューロン疾患の治療の進歩

    鈴木 直輝, 加藤 昌昭, 割田 仁, 青木 正志

    神経治療学　33　(4)　529-532　2016/07

    Publisher: 日本神経治療学会

    ISSN： 0916-8443

  138. コルチコトロピン放出ホルモン受容体1,2遺伝子における一塩基多型と過敏性腸症候群との関連

    小室葉月, 佐藤菜保子, 佐々木彩加, 鈴木直輝, 鹿野理子, 鹿野理子, 田中由佳里, 田中由佳里, 山口由美, 山口由美, 金澤素, 割田仁, 青木正志, 福土審, 福土審

    心身医学　56　(6)　636-636　2016/06/01

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  139. 過敏性腸症候群における副腎皮質刺激ホルモン放出ホルモン関連遺伝子

    佐々木彩加, 佐藤菜保子, 鈴木直輝, 金澤素, 金澤素, 青木正志, 福土審, 福土審

    心身医学　56　(3)　279-279　2016/03/01

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  140. 血中抗SRP抗体が陽性であるものの筋生検で炎症細胞浸潤が認められた筋炎の一例

    三浦智孝, 成川孝一, 加藤量広, 井泉瑠美子, 鈴木直輝, 竪山真規, 及川嵩紀

    Neuroimmunology　21　(1)　142　2016

    ISSN： 0918-936X

  141. 難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 日本人ジスフェルリン異常症の遺伝子検索への次世代シークエンサーの導入

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 小野洋也, 島倉奈緒子, 新堀哲也, 片山望, 齋藤京之, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木洋子, 三橋里美, 西野一三

    難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 平成27年度 総括・分担研究報告書　15‐16　2016

  142. 難病患者への支援体制に関する研究 難病の災害対策のあり方 宮城県神経難病医療連携センターにおける「自分で作る災害時対応ハンドブック2014年版」の活用状況調査

    青木正志, 青木正志, 関本聖子, 関本聖子, 遠藤久美子, 遠藤久美子, 椿井富美恵, 今井尚志, 今井尚志, 佐藤裕子, 榊原愛, 川内裕子, 鈴木直輝, 割田仁, 加藤昌昭, 東海林奈菜絵, 佐久間正則

    難病患者への支援体制に関する研究 平成27年度 総括・分担研究報告書　133‐138　2016

  143. 神経変性疾患領域における基盤的調査研究 家族性ALSにおける遺伝子解析

    青木正志, 鈴木直輝, 加藤昌昭, 割田仁, 井泉瑠美子, 西山亜由美, 秋山徹也, 島倉奈緒子

    神経変性疾患領域における基盤的調査研究 平成27年度 総括・分担研究報告書　66‐67　2016

  144. 原発性アミロイドーシスの1例

    斉藤有佳, 菅野重範, 宮澤康一, 渋谷聡, 下田楓美子, 井泉瑠美子, 鈴木直輝, 堅山真規

    臨床神経学(Web)　56　(11)　810(J‐STAGE)　2016

    ISSN： 1882-0654

  145. 近位筋優位の筋力低下を呈したFUS/TLS遺伝子変異を伴う家族性ALS(ALS6)の一例

    江浦信之, 泉哲石, 桐山敬生, 島倉奈緒子, 鈴木直輝, 加藤昌昭, 杉江和馬, 青木正志, 上野聡

    臨床神経学(Web)　56　(7)　528(J‐STAGE)　2016

    ISSN： 1882-0654

  146. 筋炎を初発症状とした節外性NK/T細胞リンパ腫の1例

    川口典彦, 小林理子, 石垣あや, 藤盛寿一, 井泉瑠美子, 鈴木直輝, 竪山真規, 青木正志

    臨床神経学(Web)　56　(11)　808(J‐STAGE)　2016

    ISSN： 1882-0654

  147. 日本のFUS/TLS遺伝子関連家族性ALS症例における遺伝子型-表現型相関(Genotype-phenotype correlation with FUS/TLS-linked familial ALS cases in Japan)

    秋山 徹也, 鈴木 直輝, 割田 仁, 加藤 昌昭, 西山 亜由美, 井泉 瑠美子, 池田 謙輔, 小野 洋也, 四條 友望, 青木 正志

    臨床神経学　55　(Suppl.)　S237-S237　2015/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  148. ジストロフィン異常を伴う大腿四頭筋ミオパチーの1例

    渡辺 源也, 戸恒 智子, 鍋井 敬文, 西山 修平, 鈴木 直輝, 黒田 宙, 中島 一郎, 堅山 真規, 青木 正志

    臨床神経学　55　(12)　950-950　2015/12

    Publisher: (一社)日本神経学会

    DOI： 10.5692/clinicalneurol.55_12_prpceedings2 　

    ISSN： 0009-918X

  149. Dysferlin遺伝子診断への次世代シークエンサーの活用と日本人の遺伝子変異の特徴

    高橋俊明, 井泉瑠美子, 八木沼智香子, 加藤昌昭, 島倉奈緒子, 鈴木直輝, 新堀哲也, 青木洋子, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 武田篤, 青木正志

    日本神経学会学術大会プログラム・抄録集　55　(Suppl.)　S390-S390　2015/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  150. Sporadic inclusion body myositis

    255　(5)　473-478　2015/10/31

    Publisher: 医歯薬出版

    ISSN： 0039-2359

  151. 筋炎 封入体筋炎

    青木正志, 鈴木直輝

    医学のあゆみ　255　(5)　473-478　2015/10/31

    ISSN： 0039-2359

  152. アカデミア発の創薬・研究治療 ALSに対するHGF療法

    青木正志, 割田仁, 鈴木直輝

    月刊神経内科　83　(4)　277-282　2015/10/25

    ISSN： 0386-9709

  153. Dysferlin遺伝子診断への次世代シークエンサーの導入

    高橋俊明, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 加藤昌昭, 島倉奈緒子, 鈴木直輝, 新堀哲也, 青木洋子, 小野洋也, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    国立病院総合医学会抄録集(CD-ROM)　69回　O-5　2015/10

    Publisher: 国立病院総合医学会

  154. リルゾールによる薬剤性間質性肺炎をきたした筋萎縮性側索硬化症

    澁井彩, 高井良樹, 小林潤平, 黒田宙, 鈴木直輝, 割田仁, 青木正志

    神経治療学　32　(5)　822　2015/09/25

    ISSN： 0916-8443

  155. Review/Advances in Neurological Therapeutics (2014). Motor Neuron Disease

    鈴木直輝, 加藤昌昭, 割田仁, 青木正志

    神経治療学　32　(4)　475-478　2015/07/25

    ISSN： 0916-8443

  156. 炎症性筋疾患―非感染性筋炎―多発筋炎・皮膚筋炎・封入体筋炎 封入体筋炎

    鈴木直輝, 青木正志

    日本臨床　324-328　2015/05/20

    ISSN： 0047-1852

  157. 運動ニューロン変性モデルラット脊髄微小血管のペリサイト新生

    割田仁, 四條友望, 池田謙輔, 小野洋也, 秋山徹也, 鈴木直輝, 加藤昌昭, 青木正志

    再生医療　14　336　2015/02/01

    ISSN： 1347-7919

  158. 日本神経学会制作DVD「いきる、神経内科医として」

    鈴木 直輝

    2015

  159. 小児科・産科領域疾患の大規模遺伝子解析ネットワークとエピゲノム解析拠点整備に関する研究 神経変性疾患・遺伝性筋疾患の遺伝子解析

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 加藤昌昭, 竪山真規, 割田仁, 島倉奈緒子, 安藤里紗, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子

    小児科・産科領域疾患の大規模遺伝子解析ネットワークとエピゲノム解析拠点整備に関する研究 平成26年度 委託業務成果報告書　19-20　2015

  160. Dysferlin遺伝子解析への次世代シークエンサーの導入

    高橋俊明, 井泉瑠美子, 井泉瑠美子, 八木沼智香子, 島倉奈緒子, 鈴木直輝, 新堀哲也, 青木洋子, 小野洋也, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 吉岡勝, 武田篤, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　60th　295　2015

  161. 神経変性疾患領域における基盤的調査研究 家族性ALSにおける遺伝子解析

    青木正志, 加藤昌昭, 割田仁, 鈴木直輝, 井泉瑠美子, 西山亜由美, 島倉奈緒子, 安藤里紗

    神経変性疾患領域における基盤的調査研究 平成26年度 総括・分担研究報告書　54‐56　2015

  162. 難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 日本人ジスフェルリン異常症の遺伝子変異について

    青木正志, 高橋俊明, 鈴木直輝, 井泉瑠美子, 加藤昌昭, 竪山真規, 割田仁, 島倉奈緒子, 安藤里紗, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子

    難治性筋疾患の疫学・自然歴の収集および治療開発促進を目的とした疾患レジストリー研究 平成26年度 総括・分担研究報告書　17‐18　2015

  163. 希少性難治性疾患―神経・筋難病疾患の進行抑制治療効果を得るための新たな医療機器,生体電位等で随意コントロールされた下肢装着型補助ロボット(HAL‐HN01)に関する医師主導治験の実施研究 希少疾病に対する医師主導治験における被験者リクルートについて

    青木正志, 加藤昌昭, 割田仁, 鈴木直輝, 川内裕子, 川内裕子, 佐藤裕子

    希少性難治性疾患‐神経・筋難病疾患の進行抑制治療効果を得るための新たな医療機器、生体電位等で随意コントロールされた下肢装着型補助ロボット(HAL-HN01)に関する医師主導治験の実施研究 平成26年度 総括・分担研究報告書　31‐32　2015

  164. ジストロフィン異常を伴う大腿四頭筋ミオパチーの1例

    渡辺源也, 戸恒智子, 鍋井敬文, 西山修平, 鈴木直輝, 黒田宙, 中島一郎, 竪山真規, 青木正志

    臨床神経学(Web)　55　(12)　950(J‐STAGE)　2015

    DOI： 10.5692/clinicalneurol.55_12_prpceedings2 　

    ISSN： 1882-0654

  165. Sanger法によってスクリーニングした日本人dysferlin遺伝子変異の特徴

    高橋俊明, 井泉瑠美子, 加藤昌昭, 鈴木直輝, 竪山真規, 八木沼智香子, 島倉奈緒子, 田中洋康, 吉岡勝, 今野秀彦, 武田篤, 糸山泰人, 青木正志

    日本神経学会学術大会プログラム・抄録集　54　(Suppl.)　S68-S68　2014/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  166. コルチコトロピン放出ホルモン関連遺伝子における一塩基多型と過敏性腸症候群との関連

    佐々木彩加, 佐藤菜保子, 鈴木直輝, 金澤素, 青木正志, 福土審

    心身医学　54　(12)　1151-1151　2014/12/01

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  167. 筋幹細胞特異的プロテアソーム欠損マウスの解析

    北嶋康雄, 鈴木直輝, 布宮亜樹, 田代善崇, 高橋良輔, 青木正志, 永富良一

    体力科学　63　(6)　554　2014/12/01

    ISSN： 0039-906X

  168. AZTミオパチーを発症した血友病Aの一例

    三浦明, 酒井秀章, 田中洋康, 加藤量広, 鈴木直輝, 竪山真規

    日本エイズ学会誌　16　(4)　630　2014/11/20

    ISSN： 1344-9478

  169. Dysferlinopathy in Egypt: Clinical, Pathological and Genetic characteristics

    N. A. Fahmy, A. Abd Elhady, A. Abd El-Naser, S. Ashour, A. Etribi, I. Nonaka, N. Minami, N. Suzuki, T. Takahashi, M. Aoki

    NEUROMUSCULAR DISORDERS　24　(9-10)　903-904　2014/10

    DOI： 10.1016/j.nmd.2014.06.364 　

    ISSN： 0960-8966

    eISSN： 1873-2364

  170. Sporadic inclusion body myositis and amyloid

    Aoki, M., Suzuki, N.

    Brain and Nerve　66　(7)　739-748　2014/07/01

    ISSN： 1881-6096

  171. A Loss of Function Mutation in the C9ORF72 Mouse Ortholog Results in Motor System Degeneration

    Daniel Mordes, Naoki Suzuki, Johnny Salameh, Morag Stewart, Asif Maroof, Steve Han, Robert Brown, Kevin Eggan

    JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY　73　(6)　620-620　2014/06

    ISSN： 0022-3069

    eISSN： 1554-6578

  172. Proteasome Dysfunction Induces Muscle Growth Defects And Protein Aggregation

    Yasuo Kitajima, Naoki Suzuki, Yoshitaka Tashiro, Hitoshi Warita, Masaaki Kato, Maki Tateyama, Risa Ando, Rumiko Izumi, Maya Yamazaki, Manabu Abe, Kenji Sakimura, Hidefumi Ito, Urushitani Makoto, Ryoichi Nagatomi, Ryosuke Takahashi, Masashi Aoki

    MEDICINE AND SCIENCE IN SPORTS AND EXERCISE　46　(5)　352-352　2014/05

    ISSN： 0195-9131

    eISSN： 1530-0315

  173. 変性疾患 運動ニューロン疾患 筋萎縮性側索硬化症 遺伝性ALS ALS6(FUS/TLS:fused in sarcoma/translocated in liposarcoma)

    鈴木直輝, 加藤昌昭, 割田仁, 青木正志

    日本臨床　482-486　2014/03/20

    ISSN： 0047-1852

  174. 視神経炎にて再発した自己免疫性脳炎の1例

    佐藤広隆, 藤盛寿一, 小林理子, 石垣あや, 丹治宏明, 高井良樹, 鈴木直輝, 中島一郎

    臨床神経学　54　(3)　242-242　2014/03

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  175. 骨格筋特異的プロテアソーム機能不全は筋成長不全ならびに異常タンパク質の蓄積を引き起こす

    北嶋康雄, 鈴木直輝, 田代善崇, 割田仁, 加藤昌昭, 竪山真規, 安藤里紗, 井泉瑠美子, 山崎真弥, 阿部学, 崎村建司, 伊東秀文, 漆谷真, 永富良一, 高橋良輔, 青木正志

    体力科学　63　(1)　142-142　2014/02/01

    Publisher: The Japanese Society of Physical Fitness and Sports Medicine

    DOI： 10.7600/jspfsm.63.142 　

    ISSN： 0039-906X

  176. Sanger法によってスクリーニングした日本人dysferlin遺伝子変異の特徴と本方法の問題点

    高橋俊明, 井泉瑠美子, 加藤昌昭, 鈴木直輝, 八木沼智香子, 島倉奈緒子, 谷口さやか, 大泉英樹, 田中洋康, 吉岡勝, 武田篤, 青木正志

    日本遺伝子診療学会大会プログラム・抄録集　21st　288　2014

  177. 封入体筋炎の診断基準と病態に関する最近の知見

    青木正志, 鈴木直輝, 西野一三

    日本神経学会学術大会プログラム・抄録集　55th　315　2014

  178. 病態に根ざしたALSの新規治療法開発 ALSラットモデルにおける脊髄中心管周囲の新生細胞

    青木正志, 割田仁, 水野秀紀, 加藤昌昭, 鈴木直輝, 船越洋, 岡野栄之, 糸山泰人

    神経変性疾患に関する調査研究班 分科班「病態に根ざしたALSの新規治療法開発」 平成25年度 研究報告書　5-6　2014

  179. 筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 次世代シークエンサーを用いた遠位型ミオパチーにおけるゲノム解析

    青木正志, 井泉瑠美子, 高橋俊明, 加藤昌昭, 鈴木直輝, 竪山真規, 割田仁, 島倉奈緒子, 安藤里紗, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子

    筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究 平成23-25年度 総括研究報告書　15-16　2014

  180. 筋萎縮性側索硬化症モデル成体脊髄における潜在的neurogenic niche

    割田仁, 水野秀紀, 加藤昌昭, 井泉瑠美子, 西山亜由美, 鈴木直輝, 船越洋, 糸山泰人, 青木正志

    日本神経学会学術大会プログラム・抄録集　55th　506　2014

  181. 次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 次世代シークエンサーを用いた遺伝性筋疾患におけるゲノム解析

    青木正志, 井泉瑠美子, 加藤昌昭, 割田仁, 鈴木直輝, 竪山真規, 高橋俊明, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子, 松原洋一

    次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 平成25年度 総括・分担研究報告書　11-13　2014

  182. 次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 次世代シークエンサーを用いた遺伝性筋疾患におけるゲノム解析

    青木正志, 井泉瑠美子, 加藤昌昭, 割田仁, 鈴木直輝, 竪山真規, 高橋俊明, 舟山亮, 長嶋剛史, 中山啓子, 新堀哲也, 青木洋子, 松原洋一

    次世代シークエンサーを駆使した希少遺伝性難病の原因解明と治療法開発の研究 平成23-25年度 総合研究報告書　11-14　2014

  183. Myofibrillar myopathyの大家系での次世代シークエンサーを用いた原因遺伝子の同定

    井泉 瑠美子, 新堀 哲也, 青木 洋子, 鈴木 直輝, 加藤 昌昭, 割田 仁, 高橋 俊明, 竪山 真規, 長嶋 剛史, 舟山 亮, 中山 啓子, 松原 洋一, 青木 正志

    臨床神経学　53　(12)　1450-1450　2013/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  184. 東北大学における家族性ALS遺伝子検査の検討

    加藤 昌昭, 割田 仁, 井泉 瑠美子, 島倉 奈緒子, 安藤 里紗, 鈴木 直輝, 青木 正志

    臨床神経学　53　(12)　1565-1565　2013/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  185. Dysferlinopathy患者の長期の経時的筋原性酵素と呼吸機能の推移

    高橋 俊明, 加藤 昌昭, 竪山 真規, 井泉 瑠美子, 鈴木 直輝, 八木沼 智香子, 佐藤 仁美, 島倉 奈緒子, 田中 洋康, 吉岡 勝, 今野 秀彦, 小野寺 宏, 糸山 泰人, 青木 正志

    臨床神経学　53　(12)　1580-1580　2013/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  186. 呼吸筋麻痺を伴った抗signal recognition particle(SRP)抗体陽性筋症の1例

    黒澤和大, 西山修平, 吉田隼, 大嶋龍司, 鈴木直輝, 竪山真規, 青木正志

    神経治療学　30　(5)　690　2013/09/25

    ISSN： 0916-8443

  187. 過敏性腸症候群におけるコルチコトロピン放出ホルモン関連遺伝子多型

    佐々木彩加, 佐藤菜保子, 鈴木直輝, 鹿野理子, 金澤素, 青木正志, 福土審

    東北医学雑誌　125　(1)　168-170　2013/06/25

    ISSN： 0040-8700

  188. Peripheral nerve lesions in reported cases of ALS accompanied with CIDP-like polyneuropathy

    赤石哲也, 竪山真規, 加藤量広, 三浦永美子, 井泉瑠美子, 遠藤薫, 菅野直人, 鈴木直輝, 馬場徹, 三須建郎, 菊池昭夫, 長谷川隆文, 中島一郎, 青木正志

    末梢神経　24　(1)　85-89　2013/06/01

    Publisher: 日本末梢神経学会

    ISSN： 0917-6772

  189. ラット運動ニューロン変性モデル脊髄微小血管を標的とした神経保護

    割田仁, 水野秀紀, 加藤昌昭, 鈴木直輝, 糸山泰人, 青木正志

    再生医療　12　265　2013/02/28

    ISSN： 1347-7919

  190. Expression Pattern of C9ORF72 Ortholog in Mice

    Naoki Suzuki, Asif Maroof, Kathryn Koszka, Atsushi Intoh, Kevin Eggan

    NEUROLOGY　80　2013/02

    ISSN： 0028-3878

    eISSN： 1526-632X

  191. 筋萎縮性側索硬化症モデルラット微小血管の壁細胞を標的とした運動ニューロン保護

    割田仁, 水野秀紀, 加藤昌昭, 鈴木直輝, 青木正志

    日本神経学会学術大会プログラム・抄録集　54th　533　2013

  192. Dysferlinopathy患者の長期の経時的筋原性酵素と呼吸機能の推移

    高橋俊明, 加藤昌昭, 竪山真規, 井泉瑠美子, 鈴木直輝, 八木沼智香子, 佐藤仁美, 島倉奈緒子, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 糸山泰人, 青木正志

    日本神経学会学術大会プログラム・抄録集　54th　471　2013

  193. Myofibrillar myopathyの大家系での次世代シークエンサーを用いた原因遺伝子の同定

    井泉瑠美子, 井泉瑠美子, 新堀哲也, 青木洋子, 鈴木直輝, 加藤昌昭, 割田仁, 高橋俊明, 竪山真規, 長嶋剛史, 舟山亮, 中山啓子, 松原洋一, 青木正志

    日本神経学会学術大会プログラム・抄録集　54th　332　2013

  194. 神経変性疾患に関する調査研究 FUS関連ALS症例におけるFUS,TDP‐43,ADAR2病理の免疫組織化学的検討

    郭伸, 相澤仁志, 日出山拓人, 山下雄也, 木村隆, 鈴木直輝, 青木正志

    神経変性疾患に関する調査研究 平成24年度 総括・分担研究報告書　149-151　2013

  195. 病態に根ざしたALSの新規治療法開発 ALSラットモデル脊髄における新生グリア細胞

    青木正志, 割田仁, 水野秀紀, 加藤昌昭, 鈴木直輝, 糸山泰人

    神経変性疾患に関する調査研究班分科班「病態に根ざしたALSの新規治療法開発」 平成24年度 研究報告書　5-6　2013

  196. 東北大学における家族性ALS遺伝子検査の検討

    加藤昌昭, 割田仁, 井泉瑠美子, 島倉奈緒子, 安藤里紗, 鈴木直輝, 青木正志

    日本神経学会学術大会プログラム・抄録集　54th　456　2013

  197. 骨格筋特異的プロテアソーム機能不全は筋成長不全ならびに異常タンパク質の蓄積を引き起こす

    北嶋康雄, 鈴木直輝, 田代善崇, 割田仁, 加藤昌昭, 竪山真規, 安藤里紗, 井泉瑠美子, 山崎真弥, 阿部学, 崎村建司, 伊東秀文, 漆谷真, 永富良一, 高橋良輔, 青木正志

    日本分子生物学会年会プログラム・要旨集(Web)　36th　2P-1074 (WEB ONLY)　2013

  198. Myofibrillar myopathyの大家系における次世代型シークエンサーを用いた新たな原因遺伝子の同定

    井泉瑠美子, 新堀哲也, 青木洋子, 鈴木直輝, 加藤昌昭, 割田仁, 高橋俊明, 竪山真規, 長嶋剛史, 舟山亮, 阿部康二, 中山啓子, 青木正志, 松原洋一

    日本人類遺伝学会大会プログラム・抄録集　58th　136　2013

  199. 全エクソンシークエンスによるdysferlin遺伝子変異のスクリーニング法の検討

    高橋俊明, 加藤昌昭, 西山亜由美, 井泉瑠美子, 鈴木直輝, 竪山真規, 八木沼智香子, 島倉奈緒子, 田中洋康, 吉岡勝, 今野秀彦, 糸山泰人, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　58th　189　2013

  200. ネフローゼ症候群を伴う炎症性脱髄性ニューロパチーの臨床的検討

    竪山 真規, 中島 一郎, 鈴木 直輝, 藤原 一男, 鈴木 千尋, 高野 里菜, 糸山 泰人, 青木 正志

    臨床神経学　52　(12)　1465-1465　2012/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  201. Dysferlinopathyが疑われる患者の血清CK値

    高橋 俊明, 鈴木 直輝, 加藤 昌昭, 井泉 瑠美子, 竪山 真規, 安藤 里紗, 八木沼 智香子, 佐藤 仁美, 島倉 奈緒子, 田中 洋康, 吉岡 勝, 今野 秀彦, 小野寺 宏, 西野 一三, 青木 正志

    臨床神経学　52　(12)　1548-1548　2012/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  202. 12年近いCIDP様の末梢神経障害の経過中に球症状を呈し,呼吸不全で死亡した48歳女性

    赤石哲也, 加藤量広, 三浦永美子, 井泉瑠美子, 遠藤薫, 菅野直人, 鈴木直輝, 馬場徹, 三須建郎, 菊池昭夫, 長谷川隆文, 黒田宙, 竪山真規, 中島一郎, 青木正志

    末梢神経　23　(2)　235-236　2012/12/01

    Publisher: 日本末梢神経学会

    ISSN： 0917-6772

  203. ALSの遺伝学Update

    青木 正志, 割田 仁, 鈴木 直輝, 加藤 昌昭

    臨床神経学　52　(11)　844-847　2012/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  204. 炎症性筋疾患研究の最近の進歩 封入体筋炎の病態

    鈴木直輝, 竪山真規, 井泉瑠美子, 青木正志

    月刊神経内科　77　(4)　396-404　2012/10/25

    ISSN： 0386-9709

  205. 遺伝性圧脆弱性ニューロパチーに甲状腺機能低下症を合併した一例

    金子仁彦, 菅野直人, 三須建郎, 竪山真規, 鈴木直輝, 青木正志

    臨床神経学　52　(7)　526-526　2012/07/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  206. わが国の遺伝性ALS ALS6(FUS/TLS)

    青木正志, 鈴木直輝, 加藤昌昭, 割田仁

    月刊神経内科　76　(5)　477-482　2012/05/25

    ISSN： 0386-9709

  207. 封入体筋炎―診療の現状と展望

    青木正志, 鈴木直輝

    日本臨床　70　(5)　895-906　2012/05/01

    ISSN： 0047-1852

  208. 吃音とすくみ足を呈した筋萎縮性側索硬化症の1例

    松本有史, 清水洋, 久永欣哉, 加藤量広, 鈴木直輝, 青木正志

    臨床神経学　52　(2)　123　2012/02/01

    ISSN： 0009-918X

  209. 肢帯型筋ジストロフィー2A型の1例―2B型との比較―

    高橋俊明, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 津久井伸枝, 加藤るみ子, 竪山真規, 鈴木直輝, 青木正志

    臨床神経学　52　(2)　123-123　2012/02

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  210. 日本人家族性ALSにおける遺伝子変異と臨床型の検討

    加藤昌昭, 割田仁, 鈴木直輝, 島倉奈緒子, 青木正志

    日本神経学会学術大会プログラム・抄録集　53rd　442　2012

  211. FUS P525L mutationを認めた孤発性ALSの剖検例

    相澤仁志, 木村隆, 鈴木直輝, 青木正志, 郭伸

    日本神経学会学術大会プログラム・抄録集　53rd　441　2012

  212. 神経変性疾患に関する調査研究 東北大学における家族性ALS遺伝子解析およびFUS/TLS遺伝子変異を伴う家系の検討

    青木正志, 加藤昌昭, 割田仁, 鈴木直輝, 水野秀紀, 島倉奈緒子, 今野秀彦, 加藤信介

    神経変性疾患に関する調査研究 平成23年度 総括・分担研究報告書　190-192　2012

  213. Dysferlinopathyが疑われる患者の血清CK値

    高橋俊明, 鈴木直輝, 加藤昌昭, 井泉瑠美子, 竪山真規, 安藤里紗, 八木沼智香子, 佐藤仁美, 島倉奈緒子, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 西野一三, 青木正志

    日本神経学会学術大会プログラム・抄録集　53rd　384　2012

  214. 縁取り空胞を伴う遠位型ミオパチーに対するシアル酸療法

    西野一三, 野口悟, マリクダン メイ, 森まどか, 大矢寧, 鈴木直輝, 青木正志

    日本神経学会学術大会プログラム・抄録集　53rd　186　2012

  215. 筋萎縮性側索硬化症モデルラット新生グリア細胞が形成する脊髄微小環境

    割田仁, 加藤昌昭, 鈴木直輝, 水野秀紀, 青木正志

    日本神経学会学術大会プログラム・抄録集　53rd　444　2012

  216. 病態に根ざしたALSの新規治療法開発 ALSラットモデルにおける内在性再生機転

    青木正志, 割田仁, 加藤昌昭, 鈴木直輝, 水野秀紀

    神経変性疾患に関する調査研究班 分科班「病態に根ざしたALSの新規治療法開発」 平成23年度 研究報告書　9-11　2012

  217. プリオン病のサーベイランスと感染予防に関する調査研究 東北地方におけるプリオン病のサーベイランス状況について

    青木正志, 加藤昌昭, 割田仁, 鈴木直輝, 鈴木博義

    プリオン病のサーベイランスと感染予防に関する調査研究 平成23年度 総括・分担研究報告書　54-55　2012

  218. ネフローゼ症候群を伴う炎症性脱髄性ニューロパチーの臨床的検討

    竪山真規, 中島一郎, 鈴木直輝, 藤原一男, 鈴木千尋, 高野里菜, 糸山泰人, 青木正志

    日本神経学会学術大会プログラム・抄録集　53rd　296　2012

  219. PCR‐SSCP法による日本人dysferlin遺伝子変異のスクリーニング

    高橋俊明, 鈴木直輝, 加藤昌昭, 井泉瑠美子, 竪山真規, 八木沼智香子, 佐藤仁美, 阿部恵美, 伊藤真理子, 菅原瞳, 早坂美保, 島倉奈緒子, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 糸山泰人, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　57th　134　2012

  220. 骨格筋特異的プロテアソーム機能不全は筋萎縮ならびに異常タンパク質の蓄積を引き起こす

    北嶋康雄, 鈴木直輝, 田代善崇, 割田仁, 加藤昌昭, 竪山真規, 安藤里紗, 井泉瑠美子, 山崎真弥, 阿部学, 崎村建司, 伊東秀文, 漆谷真, 永富良一, 高橋良輔, 青木正志

    日本分子生物学会年会プログラム・要旨集(Web)　35th　1W9I-8 (WEB ONLY)　2012

  221. 前頭側頭葉変性症とその関連疾患 筋萎縮性側索硬化症とFUS/TLS

    鈴木直輝, 青木正志

    日本臨床　69　389-393　2011/12/20

    ISSN： 0047-1852

  222. poloxamer188の長期持続投与によるSJLマウスの筋萎縮の抑制

    鈴木 直輝, 高橋 俊明, 竪山 真規, 割田 仁, 井泉 瑠美子, 安藤 里紗, 青木 正志

    臨床神経学　51　(12)　1302-1302　2011/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  223. 筋炎研究最近の進歩 封入体筋炎の病態と頻度

    鈴木 直輝, 竪山 真規, 割田 仁, 井泉 瑠美子, 西野 一三, 青木 正志

    臨床神経学　51　(11)　964-966　2011/11

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  224. セロトニントランスポーター遺伝子多型と中枢刺激反応性の関連

    小室葉月, 鈴木直輝, 渡辺諭史, 青木正志, 糸山泰人, 金澤素, 福土審

    心身医学　51　(11)　1049-1049　2011/11/01

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  225. Inclusion body myositis

    Suzuki, N., Aoki, M.

    Brain and Nerve　63　(11)　1205-1215　2011/11/01

    ISSN： 1881-6096

  226. ALSの治療とケア 神経栄養因子による治療法の開発

    青木正志, 割田仁, 鈴木直輝

    Clin Neurosci　29　(9)　1058-1059　2011/09/01

    ISSN： 0289-0585

  227. 家族性motor neuron diseaseが疑われ,FUS/TLS遺伝子変異を認めた26歳男性例

    原誠, 南正之, 亀井聡, 鈴木直輝, 青木正志

    臨床神経学　51　(8)　625　2011/08/01

    ISSN： 0009-918X

  228. "yes-yes"型の頭部振戦をともなった多発性硬化症の1例

    尾股 慧, 鈴木 直輝, 井泉 瑠美子, 永田 真理, 西山 修平, 中島 一郎, 糸山 泰人

    臨床神経学　51　(4)　282-285　2011/04

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  229. Clinicopathological study of 12 cases with Churg-Strauss syndrome

    渡部龍, 白井剛志, 田島結実, 藤井博司, 高澤徳彦, 石井智徳, 張替秀郎, 鈴木直輝, 竪山真規, 糸山泰人

    臨床リウマチ　23　(1)　62-67　2011/03/30

    Publisher: The Japanese Society for Clinical Rheumatology and Related Research

    DOI： 10.14961/cra.23.62 　

    ISSN： 0914-8760

    More details Close

    To clarify the clinicopathological features of Churg-Strauss syndrome (CSS), we examined 12 cases that presented with clinical features described by Churg and Strauss and also fulfilled the cristeria of American college of rheumatology. Patients, 5 male and 7 female, were 51.8 years of mean age. Anti-neutrophil cytoplasmic antibody (ANCA) was positive in 7 cases (58%, MPOANCA in 6, PR3-ANCA in1). All patients had a medical history of bronchial asthma (BA). Various organ involvements such as mononeuritis multiplex (12 cases), skin (9 cases), sinusitis (8 cases), lung and heart (5 cases, respectively), sensory organ (4 cases), central nervous system (2 cases), and gastrointestinal tract and kidney (1case, respectively) were observed. ANCA positive patients had significantly higher prevalence of skin involvement than ANCA negative patients. We also observed a tendency of ANCA negative patients having a higher frequency of lung and heart lesion.<br>    Skin biopsy was performed in6cases.Extravascular infiltration of eosinophils was observed in all of them, but necrotizing vasculitis and extravascular granuloma, which is thought to be characteristic to CSS, was observed in only1case, respectively. Neural biopsy was done in 4 cases. Almost all the cases showed axonal degeneration and decrease of nerve fiber density, but no cases showed necrotizing vasculitis and extravascular granuloma.<br>    In conclusion, various types of organ involvement were observed in12cases with CSS, but typical pathological changes such as necrotizing vasculitis and extravascular granuloma were not common in CSS.

  230. 卵巣奇形腫摘出後に症状の改善を認めた急性脳症の2症例

    西本光男, 高橋尚美, 永瀬智, 武田卓, 八重樫伸生, 井泉瑠美子, 加藤量広, 鈴木直輝, 中島一郎, 黒田宙, 高橋幸利

    北海道産科婦人科学会会誌　55　(1)　86-87　2011/03

    ISSN： 0367-6277

  231. 潜在性RBDを呈したFALSの一例

    上田素子, 森田ゆかり, 大崎康史, 大川真理, 土居義典, 島倉奈緒子, 鈴木直輝, 青木正志

    臨床神経学　51　(2)　158-158　2011/02/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  232. FUS/TLS遺伝子変異を認めた筋萎縮性側索硬化症の親子例

    松本有史, 瀬野暢仁, 及川崇紀, 清水洋, 久永欣哉, 鈴木直輝, 島倉奈緒子, 金森洋子, 青木正志

    臨床神経学　51　(2)　162　2011/02/01

    ISSN： 0009-918X

  233. 反復性高CK血症を呈し,頸部前項屈脱力が特徴であった脂質蓄積性ミオパチーの1例

    永田真理, 井泉瑠美子, 鈴木直輝, 竪山真規, 長谷川隆文, 望月廣

    臨床神経学　51　(2)　163　2011/02/01

    ISSN： 0009-918X

  234. 筋萎縮性側索硬化症モデルラットの慢性進行性脱神経筋における再生反応

    割田仁, 水野秀紀, 鈴木直輝, 糸山泰人, 青木正志

    再生医療　10　248　2011/02/01

    ISSN： 1347-7919

  235. FUS/TLS遺伝子異常に伴う日本人家族性ALSにおける遺伝子変異と臨床型,病理に関する検討

    青木正志, 鈴木直輝, 割田仁, 加藤昌昭, 水野秀紀, 島倉奈緒子, 今野秀彦, 加藤信介, 糸山泰人

    日本神経学会学術大会プログラム・抄録集　52nd　282　2011

  236. poloxamer188の長期持続投与によるSJLマウスの筋萎縮の抑制

    鈴木直輝, 高橋俊明, 竪山真規, 割田仁, 井泉瑠美子, 安藤里紗, 青木正志

    日本神経学会学術大会プログラム・抄録集　52nd　367　2011

  237. 「筋萎縮性側索硬化症の病態に基づく画期的治療法の開発」血管新生因子によるALSモデルラット神経保護の試み

    青木正志, 割田仁, 水野秀紀, 鈴木直輝, 糸山泰人, 船越洋, 中村敏一

    筋萎縮性側索硬化症の病態に基づく画期的治療法の開発 平成22年度 総括研究報告書　31-34　2011

  238. 筋萎縮性側索硬化症モデルラットにおける骨格筋再生

    割田仁, 水野秀紀, 鈴木直輝, 糸山泰人, 青木正志

    日本神経学会学術大会プログラム・抄録集　52nd　382　2011

  239. 封入体筋炎の病態と頻度

    鈴木直輝

    日本神経学会学術大会プログラム・抄録集　52nd　173　2011

  240. 精神・神経疾患のiPS細胞を用いた診断・治療法の開発に関する戦略的研究 選択的運動ニューロン変性モデルにおける神経再生誘導に適切な細胞外微小環境構築の試み

    青木正志, 割田仁, 鈴木直輝

    精神・神経疾患研究開発費による研究報告集(2年度班・初年度班) 平成22年度　56　2011

  241. 筋ジストロフィーおよびその関連疾患の分子病態解明,診断法確立と薬物治療の開発に関する研究 ジスフェルリノパチー病態の解明およびその治療に関する研究

    青木正志, 高橋俊明, 鈴木直輝, 竪山真規, 割田仁, 八木沼智香子, 早坂美保, 佐藤仁美, 相場瞳, 伊藤真理子, 阿部恵美, 吉岡勝, 今野秀彦, 小野寺宏, 武田伸一, 林由起子, 西野一三, 糸山泰人

    筋ジストロフィーおよびその関連疾患の分子病態解明、診断法確立と薬物治療の開発に関する研究 平成20-22年度 総括研究報告書　16-17　2011

  242. 神経変性疾患に関する調査研究 FUS/TLS遺伝子異常に伴う日本人家族性ALSにおける遺伝子変異と臨床型,病理に関する検討

    青木正志, 鈴木直輝, 割田仁, 加藤昌昭, 水野秀紀, 島倉奈緒子, 今野秀彦, 加藤信介, 糸山泰人

    神経変性疾患に関する調査研究 平成22年度 総括・分担研究報告書　65-67　2011

  243. 「筋萎縮性側索硬化症の病態に基づく画期的治療法の開発」細胞外微小環境と内在性神経幹/前駆細胞を標的としたALS再生誘導療法開発の試み

    糸山泰人, 青木正志, 割田仁, 水野秀紀, 鈴木直輝, 船越洋, 中村敏一

    筋萎縮性側索硬化症の病態に基づく画期的治療法の開発 平成20-22年度 総合研究報告書　45-49　2011

  244. 日本人三好型遠位型筋ジストロフィーの遺伝子変異の特徴と自然歴―肢帯型筋ジストロフィー2B型との比較―

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 吉岡勝, 今野秀彦, 小野寺宏, 西野一三, 糸山泰人

    日本神経学会学術大会プログラム・抄録集　52nd　366　2011

  245. Dysferlinopathyが疑われるもののdysferlin遺伝子変異の確定しなかった患者の検討

    高橋俊明, 鈴木直輝, 井泉瑠美子, 竪山真規, 安藤里紗, 八木沼智香子, 佐藤仁美, 島倉奈緒子, 田中洋康, 吉岡勝, 小野寺宏, 西野一三, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　56th　162　2011

  246. 特定疾患患者の自立支援体制の確立に関する研究 神経・筋難病の患者会支援の試み

    青木正志, 関本聖子, 遠藤久美子, 佐藤裕子, 久田葉子, 五十嵐ひとみ, 仙石美枝子, 今井尚志, 椿井富美恵, 川内裕子, 割田仁, 鈴木直輝, 金森洋子, 糸山泰人

    特定疾患患者の自立支援体制の確立に関する研究 平成22年度総括・分担研究報告書　29-34　2011

  247. 日本人家族性ALSにおける遺伝子変異と臨床型,病理に関する検討

    島倉奈緒子, 鈴木直輝, 加藤昌昭, 割田仁, 水野秀紀, 今野秀彦, 加藤信介, 糸山泰人, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　56th　197　2011

  248. 日本における封入体筋炎の臨床・病理学的特徴の検討

    鈴木 直輝, 青木 正志, 竪山 真規, 割田 仁, 井泉 瑠美子, 秋山 徹也, 新井 法子, 糸山 泰人, 森 まどか, 日下 博文, 樋口 逸郎, 近藤 智善, 内野 誠, 梶 龍兒, 西野 一三

    臨床神経学　50　(12)　1137-1137　2010/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  249. 経過中にネフローゼ症候群を伴った亜急性再発性多発根神経炎の一例

    中島一郎, 竪山真規, 鈴木直輝, 藤原一男, 鈴木千尋, 高野里菜, 青木正志, 糸山泰人

    末梢神経　21　(2)　276-277　2010/12/01

    ISSN： 0917-6772

  250. 当科におけるChurg‐Strauss症候群12例の臨床病理学的検討

    渡部龍, 白井剛志, 田島結実, 藤井博司, 高澤徳彦, 鈴木直輝, 竪山真規, 糸山泰人, 石井智徳, 張替秀郎

    末梢神経　21　(2)　247-248　2010/12/01

    ISSN： 0917-6772

  251. 肝細胞増殖因子による筋萎縮性側索硬化症に対する新規治療法の開発

    青木正志, 割田仁, 鈴木直輝, 水野秀紀, 船越洋, 中村雅也, 岡野栄之, 糸山泰人

    日本人類遺伝学会大会プログラム・抄録集　55th　160　2010/10/08

  252. 三好型遠位型筋ジストロフィーの自然経過

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 八木沼智香子, 早坂美保, 佐藤仁美, 菅原瞳, 伊藤真理子, 阿部恵美, 吉岡勝, 今野秀彦, 小野寺宏, 西野一三, 糸山泰人

    日本人類遺伝学会大会プログラム・抄録集　55th　190　2010/10/08

  253. Clinical features of limb-girdle muscular dystrophy type 2B with the c.2997G &gt; T mutation

    T. Takahashi, M. Aoki, N. Suzuki, C. Yaginuma, H. Sato, M. Hayasaka, H. Sugawara, E. Abe, M. Ito, M. Tateyama, M. Yoshioka, H. Konno, H. Onodera, Y. Itoyama

    NEUROMUSCULAR DISORDERS　20　(9-10)　606-606　2010/10

    DOI： 10.1016/j.nmd.2010.07.035 　

    ISSN： 0960-8966

  254. Prevalence of inclusion body myositis (IBM) in Japanese population

    N. Suzuki, M. Aoki, M. Tateyama, R. Izumi, H. Warita, Y. Itoyama, M. Mori, H. Kusaka, I. Higuchi, T. Kondo, M. Uchino, R. Kaji, I. Nishino

    NEUROMUSCULAR DISORDERS　20　(9-10)　631-631　2010/10

    DOI： 10.1016/j.nmd.2010.07.113 　

    ISSN： 0960-8966

  255. DMRV and GNE mutations: genotype-phenotype correlation in 100 Japanese patients

    H. Tomimitsu, A. Arai, K. Murayama, J. Shimizu, N. Suzuki, T. Nagata, M. Aoki, H. Mizusawa, K. Tanaka, I. Nishino

    NEUROMUSCULAR DISORDERS　20　(9-10)　619-619　2010/10

    DOI： 10.1016/j.nmd.2010.07.076 　

    ISSN： 0960-8966

  256. パーキンソン病の運動症状出現前に認められたactecollisの検討

    菅野直人, 加藤量広, 三浦永美子, 川口典彦, 井泉瑠美子, 鈴木直輝, 割田仁, 中島一郎, 武田篤

    臨床神経生理学　38　(5)　328　2010/10/01

    ISSN： 1345-7101

  257. 視床失語を呈したtumefactive demyelinating diseaseの1例

    加藤量広, 菅野直人, 井泉瑠美子, 馬場徹, 高井良樹, 三須建郎, 鈴木直輝, 長谷川隆文, 中島一郎, 糸山泰人, 園田順彦, 隈部俊宏, 渡辺みか

    臨床神経学　50　(8)　597-597　2010/08/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  258. PABPN1遺伝子のGCNリピートの非延長を確認した眼咽頭遠位型ミオパチーの1例

    高橋俊明, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 八木沼智香子, 早坂美保, 佐藤仁美, 小野寺淳一, 大沼歩, 千田圭二, 小林和夫, 竪山真規, 鈴木直輝, 青木正志, 糸山泰人

    臨床神経学　50　(3)　205-205　2010/03

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  259. 全身倦怠感が主訴であったMcArdle病の1例

    井泉瑠美子, 鈴木直輝, 加藤量広, 割田仁, 竪山真規, 中島一郎, 糸山泰人

    臨床神経学　50　(3)　205　2010/03/01

    ISSN： 0009-918X

  260. 末梢神経障害,筋痙攣,小脳・頸胸髄萎縮を伴う家族性運動失調の一家系

    加藤量広, 鈴木直輝, 井泉瑠美子, 割田仁, 竪山真規, 中島一郎, 糸山泰人, 古澤嘉彦

    臨床神経学　50　(3)　202　2010/03/01

    ISSN： 0009-918X

  261. 筋萎縮性側索硬化症モデルラット脊髄における微小血管新生

    割田仁, 青木正志, 水野秀紀, 鈴木直輝, 船越洋, 中村敏一, 糸山泰人

    再生医療　9　279　2010/02/05

    ISSN： 1347-7919

  262. 筋ジストロフィーの臨床試験実施体制構築に関する研究 日本人のジスフェルリン遺伝子変異の確定した肢帯型筋ジストロフィー2B型の特徴

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 竪山真規, 八木沼智香子, 早坂美保, 佐藤仁美, 相場瞳, 阿部恵美, 伊藤真理子, 松村剛, 久留聡, 吉岡勝, 今野秀彦, 小野寺宏, 糸山泰人

    厚生労働省精神・神経疾患研究委託費による研究報告集 平成21年度 (2年度班・初年度班)　339　2010

  263. 神経変性疾患に関する調査研究 若年発症・急速進行・好塩基性封入体を特徴としFUS遺伝子に変異を伴う日本人家族性筋萎縮性側索硬化症の5家系

    青木正志, 鈴木直輝, 割田仁, 加藤昌昭, 水野秀紀, 島倉奈緒子, 秋山徹也, 古谷博和, 鉾之原敏博, 岩城明子, 服巻保幸, 富樫慎二, 今野秀彦, 糸山泰人

    神経変性疾患に関する調査研究 平成21年度 総括・分担研究報告書　55-57　2010

  264. 日本人のdysferlin遺伝子変異の確定した肢帯型筋ジストロフィー2B型の特徴

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 吉岡勝, 今野秀彦, 林由起子, 西野一三, 埜中征哉, 小野寺宏, 糸山泰人

    日本神経学会総会プログラム・抄録集　51st　183　2010

  265. 経過中にネフローゼ症候群を伴った亜急性再発性多発根神経炎の一例

    中島一郎, 竪山真規, 鈴木直輝, 藤原一男, 鈴木千尋, 高野里菜, 青木正志, 糸山泰人

    日本末梢神経学会学術集会プログラム・抄録　21st　56　2010

  266. 日本における封入体筋炎の臨床・病理学的特徴の検討

    鈴木直輝, 青木正志, 竪山真規, 割田仁, 井泉瑠美子, 秋山徹也, 新井法子, 糸山泰人, 森まどか, 日下博文, 樋口逸郎, 近藤智善, 内野誠, 梶龍兒, 西野一三

    日本神経学会総会プログラム・抄録集　51st　234　2010

  267. 精神・神経疾患のiPS細胞を用いた診断・治療法の開発に関する戦略的研究 選択的運動ニューロン変性モデルにおける神経再生誘導に適切な細胞外微小環境構築の試み

    青木正志, 割田仁, 水野秀紀, 鈴木直輝, 糸山泰人

    厚生労働省精神・神経疾患研究委託費による研究報告集 平成21年度 (2年度班・初年度班)　499　2010

  268. FUS遺伝子変異によるALSの1家系

    荒木栄一, 荒畑創, 古谷博和, 藤井直樹, 鈴木直輝, 青木正志, 糸山泰人

    日本神経学会総会プログラム・抄録集　51st　179　2010

  269. 微小血管新生促進によるALSモデルラット神経保護の試み

    割田仁, 青木正志, 水野秀紀, 鈴木直輝, 船越洋, 中村敏一, 糸山泰人

    日本神経学会総会プログラム・抄録集　51st　299　2010

  270. 急激に社会問題化している心身症の克服モデル セロトニントランスポーター遺伝子多型とストレス感受性に関する研究

    青木正志, 鈴木直輝, 糸山泰人, 小室葉月, 河野優子, 水野資子, 鹿野理子, 金澤素, 福土審

    急激に社会問題化している心身症の克服モデル 平成21年度研究成果報告書　34-36　2010

  271. Crohn病の長期経過後にアミロイドミオパチーを呈した一剖検例

    加藤量広, 鈴木直輝, 井泉瑠美子, 中島一郎, 竪山真規, 藤原一男, 糸山泰人, 中村保宏

    日本末梢神経学会学術集会プログラム・抄録　21st　74　2010

  272. 当科におけるChurg‐Strauss症候群12例の臨床病理学的検討

    渡部龍, 白井剛志, 田島結実, 藤井博司, 高澤徳彦, 鈴木直輝, 竪山真規, 糸山泰人, 石井智徳, 張替秀郎

    日本末梢神経学会学術集会プログラム・抄録　21st　48　2010

  273. 若年発症・急速進行・好塩基性封入体を特徴としFUS遺伝子変異を伴う家族性ALSの5家系

    青木正志, 鈴木直輝, 割田仁, 加藤昌昭, 水野秀紀, 島倉奈緒子, 秋山徹也, 今野秀彦, 糸山泰人

    日本神経学会総会プログラム・抄録集　51st　179　2010

  274. 特定疾患患者の自立支援体制の確立に関する研究 神経・筋難病の患者会支援の試み

    青木正志, 関本聖子, 遠藤久美子, 佐藤裕子, 遠藤早苗, 五十嵐ひとみ, 仙石美枝子, 今井尚志, 椿井富美恵, 割田仁, 鈴木直輝, 金森洋子, 糸山泰人

    特定疾患患者の自立支援体制の確立に関する研究 平成21年度総括・分担研究報告書　15-19　2010

  275. 筋萎縮性側索硬化症患者の遺伝子・生体試料バンクの構築に関する研究

    青木正志, 鈴木直輝, 割田仁, 糸山泰人

    筋萎縮性側索硬化症患者の遺伝子・生体試料バンクの構築 平成21年度 総括・分担研究報告書　5-7　2010

  276. 筋萎縮性側索硬化症の病態に基づく画期的治療法の開発 再生誘導因子の逐次投与によるALSラットモデル内在性再生機転促進の試み

    糸山泰人, 青木正志, 割田仁, 水野秀紀, 鈴木直輝, 船越洋, 中村敏一

    筋萎縮性側索硬化症の病態に基づく画期的治療法の開発 平成21年度 総括研究報告書　10-12　2010

  277. 発症前長期にわたりAQP4抗体が陽性であったNMOの1例

    西山 修平, 伊藤 孝, 三須 建郎, 高橋 利幸, 菊池 昭夫, 鈴木 直輝, 神 一敬, 青木 正志, 藤原 一男, 糸山 泰人

    臨床神経学　49　(12)　1035-1035　2009/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  278. Development of Motor Neuron Restorative Therapy in Amyotrophic Lateral Sclerosis Using Hepatocyte Growth Factor

    青木正志, 割田仁, 水野秀紀, 石垣あや, 鈴木直輝, 糸山泰人

    神経治療学　26　(6)　725-729　2009/11/25

    ISSN： 0916-8443

  279. ジスフェルリン遺伝子解析における全エクソンシークエンス法とSSCPスクリーニング法との比較

    八木沼智香子, 高橋俊明, 佐藤仁美, 早坂美保, 相場瞳, 遠藤重喜, 鈴木直輝, 吉岡勝, 青木正志, 今野秀彦, 小野寺宏, 糸山泰人

    国立病院総合医学会講演抄録集　63回　378-378　2009/10

    Publisher: 国立病院総合医学会

  280. Dislocation of neuronal nitric oxide synthase contributes to muscle atrophy in amyotrophic lateral sclerosis

    N. Suzuki, M. Aoki, H. Warita, S. Takeda, Y. Itoyama

    NEUROMUSCULAR DISORDERS　19　(8-9)　566-566　2009/09

    DOI： 10.1016/j.nmd.2009.06.075 　

    ISSN： 0960-8966

  281. 眼球運動失行と低アルブミン血症を伴う早発型脊髄小脳失調症(EAOH/AOA1)の1例

    吉岡勝, 高橋俊明, 今野秀彦, 田中洋康, 小野寺宏, 鈴木直輝, 島倉奈緒子, 青木正志, 糸山泰人

    臨床神経学　49　(8)　503-503　2009/08

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  282. 高齢で発症した遺伝性圧脆弱性ニューロパチーの2例

    川口典彦, 鈴木直輝, 竪山真規, 高井良樹, 水野秀紀, 松田基弘, 三須建郎, 中島一郎, 糸山泰人

    臨床神経学　49　(8)　504-504　2009/08/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  283. 内臓刺激に対する中枢反応におけるセロトニントランスポーター遺伝子多型の影響

    小室葉月, 鈴木直輝, 渡辺諭史, 青木正志, 糸山泰人, 金澤素, 福土審

    心身医学　49　(6)　533-533　2009/06/01

    Publisher: (一社)日本心身医学会

    ISSN： 0385-0307

  284. ALSラットに対するフリーラジカルスカベンジャー,edaravonの効果

    青木正志, 割田仁, 水野秀紀, 鈴木直輝, 幸敏志, 高橋郁夫, 糸山泰人

    神経治療学　26　(3)　362　2009/05/25

    ISSN： 0916-8443

  285. Marfan's syndrome with CSF hypovolemia headache due to dural ectasia.

    加藤量広, 鈴木直輝, 遠藤薫, 青木正志, 糸山泰人

    月刊神経内科　70　(4)　417-418　2009/04/25

    ISSN： 0386-9709

  286. 発症前長期にわたりAQP4抗体が陽性であったNMOの1例

    西山修平, 伊藤孝, 三須建郎, 高橋利幸, 菊池昭夫, 鈴木直輝, 神一敬, 青木正志, 藤原一男, 糸山泰人

    Neuroimmunology　17　(1)　81　2009/03/01

    ISSN： 0918-936X

  287. 高齢発症重症筋無力症における胸腺摘出術の予後の検討

    高井良樹, 中島一郎, 鈴木直輝, 藤原一男, 糸山泰人

    Neuroimmunol　17　(1)　129　2009/03/01

    ISSN： 0918-936X

  288. S-V-3 Neuronal nitric oxide synthase (nNOS) is a regulator of skeletal muscle mass(The Proceedings of the 17th Annual Meetings of Japan Society of Exercise and Sports Physiology Jury 25-26, (Tokyo)) :

    MIYAGOE-SUZUKI Yuko, ITO Naoki, SUZUKI Naoki, TAKEDA Shin'ichi

    Advances in exercise and sports physiology　15　(2)　47-47　2009

    Publisher: Japan Society of Exercise and Sports Physiology

    ISSN： 1340-3141

  289. Aquaporin-4-antibody seroconversion occurs before the onset of neuromyelitis optica

    S. Nishiyama, A. Kikuchi, N. Suzuki, K. Jin, M. Aoki, T. Takahashi, T. Misu, K. Fujihara, Y. Itoyama

    MULTIPLE SCLEROSIS　15　(1)　145-145　2009/01

    ISSN： 1352-4585

  290. 肢帯型筋ジストロフィー2B型におけるG3370T変異と臨床経過

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 吉岡勝, 今野秀彦, 林由起子, 西野一三, 埜中征哉, 小野寺宏, 糸山泰人

    日本神経学会総会プログラム・抄録集　50th　211　2009

  291. 神経型一酸化窒素合成酵素(nNOS)は骨格筋の可塑性の制御因子である

    鈴木友子, 伊藤尚基, 武田伸一, 鈴木直輝

    日本運動生理学会大会プログラム・抄録集　17th　52　2009

  292. Dysferlinopathyにおけるミスセンス変異と発症年齢の検討

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 八木沼智香子, 早坂美保, 佐藤仁美, 相場瞳, 伊藤真理子, 阿倍恵美, 松村剛, 林由起子, 西野一三, 埜中征哉, 吉岡勝, 今野秀彦, 小野寺宏, 糸山泰人

    日本人類遺伝学会大会プログラム・抄録集　54th　174　2009

  293. 発症前長期にわたりAQP4抗体が陽性であったNMOの1例

    西山修平, 伊藤孝, 三須建郎, 高橋利幸, 菊池昭夫, 鈴木直輝, 神一敬, 青木正志, 藤原一男, 糸山泰人

    日本神経学会総会プログラム・抄録集　50th　190　2009

  294. 筋萎縮性側索硬化症マウスに対する一酸化窒素合成酵素阻害剤による治療の検討

    鈴木直輝, 青木正志, 割田仁, 水野秀紀, 武田伸一, 糸山泰人

    日本神経学会総会プログラム・抄録集　50th　175　2009

  295. 若年発症・急速進行・好塩基性封入体を特徴としFUS/TLSに変異を持つ日本人家族性筋萎縮性側索硬化症の3家系

    鈴木直輝, 青木正志, 割田仁, 加藤昌昭, 水野秀紀, 島倉奈緒子, 秋山徹也, 古谷博和, 鉾之原敏博, 岩城明子, 服巻保幸, 富樫慎二, 今野秀彦, 糸山泰人

    日本人類遺伝学会大会プログラム・抄録集　54th　200　2009

  296. 神経変性疾患に関する調査研究 筋萎縮性側索硬化症マウスを用いた一酸化窒素合成酵素阻害剤による治療法の開発

    青木正志, 鈴木直輝, 割田仁, 水野秀紀, 武田伸一, 糸山泰人

    神経変性疾患に関する調査研究 平成20年度 総括・分担研究報告書　103-105　2009

  297. 重症難病患者の地域医療体制の構築に関する研究班 東北大学病院地域医療連携センターヘの難病担当看護師配置の試み

    糸山泰人, 青木正志, 佐藤裕子, 遠藤早苗, 仙石美枝子, 関本聖子, 遠藤久美子, 割田仁, 水野秀紀, 鈴木直輝, 金森洋子

    重症難病患者の地域医療体制の構築に関する研究班 平成20年度 総括・分担研究報告書　23　2009

  298. 特定疾患患者の自立支援体制の確立に関する研究 神経・筋難病の患者会支援の試み

    青木正志, 関本聖子, 遠藤久美子, 佐藤裕子, 遠藤早苗, 五十嵐ひとみ, 仙石美枝子, 今井尚志, 椿井富美恵, 割田仁, 水野秀紀, 鈴木直輝, 金森洋子, 糸山泰人

    特定疾患患者の自立支援体制の確立に関する研究 平成20年度総括・分担研究報告書　15-18　2009

  299. 急激に社会問題化している心身症の克服モデル セロトニントランスポーター遺伝子多型とストレス感受性に関する研究

    青木正志, 小室葉月, 福土審, 鈴木直輝, 糸山泰人

    急激に社会問題化している心身症の克服モデル 平成20年度総括・分担研究報告書　33-36　2009

  300. Dysferlinopathyの簡易遺伝子スクリーニング法の開発

    林 紗織, 大澤 裕, 岡田 只士, 久我 敦, 村上 龍文, 鈴木 直輝, 高橋 俊明, 青木 正志, 砂田 芳秀

    臨床神経学　48　(12)　1232-1232　2008/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  301. Sjoegren症候群を合併したCADASILの2例

    川口典彦, 高井良樹, 鈴木直輝, 菊池昭夫, 竪山真規, 青木正志, 中島一郎, 糸山泰人

    臨床神経学　48　(10)　458-758　2008/10/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  302. 口唇ヘルペス感染に伴って橋内三叉神経路病変を来した再発性脊髄炎の1例

    上野聖平, 水野秀紀, 鈴木直輝, 田野大人, 三須建郎, 藤原一男, 中島一郎, 糸山泰人

    臨床神経学　48　(10)　762-762　2008/10/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  303. Aquaporin-4-antibody seroconversion occurs before the onset of neuromyelitis optica

    Shuhei Nishiyama, Akio Kikuchi, Naoki Suzuki, Kazutaka Jin, Masashi Aoki, Toshiyuki Takahashi, Tatsuro Misu, Kazuo Fujihara, Yasuto Itoyama

    MULTIPLE SCLEROSIS　14　S237-S237　2008/09

    ISSN： 1352-4585

  304. 神経線維腫症I型にて進行性四肢麻痺をきたした1例

    西山修平, 鈴木直輝, 池西太郎, 小澤浩司, 竪山真規, 青木正志, 糸山泰人

    臨床神経学　48　(7)　521　2008/07/01

    ISSN： 0009-918X

  305. 成人型Pompe病に対する酵素補充療法の治療経験

    遠藤薫, 鈴木直輝, 金岡千尋, 西山修平, 青木正志, 竪山真規, 糸山泰人, 福田冬季子, 杉江秀夫, 埜中征哉, 西野一三

    臨床神経学　48　(7)　521-521　2008/07

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  306. 症候性過眠症で発症したTumefactive demyelinating lesionの1例

    金岡千尋, 鈴木直輝, 藤原一男, 糸山泰人

    神経治療学　25　(3)　276　2008/05/25

    ISSN： 0916-8443

  307. 筋ジストロフィー治療のエビデンス構築に関する臨床研究 日本人のジスフェルリン遺伝子変異の確定した肢帯型筋ジストロフィーの臨床経過および治療的介入の効果

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 竪山真規, 早坂美保, 佐藤仁美, 相場瞳, 阿部恵美, 伊藤真理子, 松村剛, 久留聡, 吉岡勝, 今野秀彦, 小野寺宏, 糸山泰人

    筋ジストロフィー治療のエビデンス構築に関する臨床研究 平成17-19年度 総括研究報告書　271-272　2008

  308. 筋ジストロフィー治療のエビデンス構築に関する臨床研究 日本人のジスフェルリン遺伝子変異の特徴とジスフェルリン遺伝子変異の確定した肢帯型筋ジストロフィーの臨床経過

    高橋俊明, 青木正志, 神位りえ子, 小野寺好明, 鈴木直輝, 堅山真規, 相場瞳, 佐藤仁美, 阿部恵美, 伊藤真理子, 松村剛, 久留聡, 今野秀彦, 小野寺宏, 糸山泰人

    筋ジストロフィー治療のエビデンス構築に関する臨床研究 平成17-19年度 総括研究報告書　211　2008

  309. 筋ジストロフィー治療のエビデンス構築に関する臨床研究 ジスフェルリン遺伝子変異の確定した肢帯型筋ジストロフィーの自然経過および治療的介入の検証

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 竪山真規, 相場瞳, 佐藤仁美, 早坂美保, 近藤恵美, 伊藤真理子, 松村剛, 久留聡, 今野秀彦, 木村格, 糸山泰人

    筋ジストロフィー治療のエビデンス構築に関する臨床研究 平成17-19年度 総括研究報告書　154　2008

  310. 肢帯型筋ジストロフィー2B型におけるG3370T(W999C)変異と臨床経過

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 八木沼智香子, 早坂美保, 佐藤仁美, 相場瞳, 伊藤真理子, 阿部恵美, 松村剛, 林由起子, 西野一三, 埜中征哉, 吉岡勝, 今野秀彦, 小野寺宏, 糸山泰人

    日本人類遺伝学会大会プログラム・抄録集　53rd　141　2008

  311. 筋ジストロフィー治療のエビデンス構築に関する臨床研究 日本人のジスフェルリン遺伝子変異の確定した肢帯型筋ジストロフィーの遺伝子変異の特徴と臨床経過および治療的介入の検証

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 竪山真規, 早坂美保, 佐藤仁美, 相場瞳, 阿部恵美, 伊藤真理子, 松村剛, 久留聡, 吉岡勝, 今野秀彦, 小野寺宏, 糸山泰人

    筋ジストロフィー治療のエビデンス構築に関する臨床研究 平成17-19年度 論文集　219-222　2008

  312. 筋ジストロフィーおよびその関連する疾患の病態生理の解明と治療薬物の開発に関する研究 II.ジストロフィノパチー/肢帯型筋ジストロフィー 肢帯型筋ジストロフィーを表現型とする日本人dysferlinopathyの特徴

    青木正志, 高橋俊明, 鈴木直輝, 竪山真規, 早坂美保, 佐藤仁美, 相場瞳, 阿部(近藤, 恵美, 伊藤真理子, 吉岡勝, 今野秀彦, 小野寺宏, 林由起子, 西野一三, 糸山泰人

    筋ジストロフィーおよびその関連する疾患の病態生理の解明と治療薬物の開発に関する研究 清水班 平成17-19年度研究報告書　35-36　2008

  313. 日本人のdysferlin遺伝子変異の確定した肢帯型筋ジストロフィーの臨床経過

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 吉岡勝, 今野秀彦, 林由起子, 西野一三, 埜中征哉, 小野寺宏, 糸山泰人

    日本神経学会総会プログラム・抄録集　49th　322　2008

  314. nNOS/NOを介した除神経による筋萎縮の解析

    鈴木直輝, 青木正志, 鈴木友子, 武田伸一, 糸山泰人

    日本神経学会総会プログラム・抄録集　49th　257　2008

  315. Dysferlinopathyの簡易遺伝子スクリーニング法の開発

    林紗織, 大澤裕, 岡田只士, 久我敦, 村上龍文, 鈴木直輝, 高橋俊明, 青木正志, 砂田芳秀

    日本神経学会総会プログラム・抄録集　49th　322　2008

  316. 急激に社会問題化している心身症の克服モデル セロトニントランスポーターの遺伝子多型とストレス感受性に関する研究

    青木正志, 小室葉月, 福土審, 鈴木直輝, 糸山泰人

    急激に社会問題化している心身症の克服モデル 平成19年度研究成果報告書　29-32　2008

  317. 全身性エリテマトーデス(SLE)に合併したCIDPの一例

    竪山真規, 鈴木直輝, 鈴木一之, 糸山泰人

    末梢神経　18　(2)　194-197　2007/12/01

    ISSN： 0917-6772

  318. 強直脊椎を呈した肢帯型筋ジストロフィー1B型の1例

    高橋俊明, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 小野寺好明, 鈴木直輝, 竪山真規, 青木正志, 糸山泰人

    国立病院総合医学会講演抄録集　61回　358-358　2007/11

    Publisher: 国立病院総合医学会

  319. Rigid spineを呈した肢帯型筋ジストロフィー1B型の1例

    高橋俊明, 田中洋康, 吉岡勝, 今野秀彦, 小野寺宏, 小野寺好明, 鈴木直輝, 竪山真規, 青木正志, 糸山泰人

    臨床神経学　47　(6)　379-379　2007/06

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  320. Gene therapy for Duchenne muscular dystrophy

    Naoki Suzuki, Yuko Miyagoe-Suzuki, Shin'ichi Takeda

    Future Neurology　2　(1)　87-96　2007/01

    DOI： 10.2217/14796708.2.1.87 　

    ISSN： 1479-6708

  321. Nitric oxide production results in disuse-induced muscle atrophy through dislocation of neuronal nitric oxide synthase

    Naoki Suzuki, Norio Motohashi, Yuko Suzuki, Yasuto Itoyama, Masashi Aoki, Shin'ichi Takeda

    NEUROSCIENCE RESEARCH　58　S177-S177　2007

    ISSN： 0168-0102

  322. 全身性エリテマトーデス(SLE)に合併したCIDPの一例

    竪山真規, 鈴木直輝, 小野寺好明, 糸山泰人, 鈴木一之

    日本末梢神経学会学術集会プログラム・抄録　18th　53　2007

  323. 肢帯型筋ジストロフィー2B型におけるdysferlin遺伝子変異と臨床型の関係

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 竪山真規, 吉岡勝, 今野秀彦, 林由起子, 西野一三, 埜中征哉, 小野寺宏, 糸山泰人

    日本神経学会総会プログラム・抄録集　48th　214　2007

  324. nNOS/NOを介した筋萎縮の分子機構の解析

    鈴木直輝, 青木正志, 鈴木友子, 糸山泰人, 武田伸一

    日本神経学会総会プログラム・抄録集　48th　278　2007

  325. 肢帯型筋ジストロフィー2B型の軽症型となるG3370T(W999C)変異の臨床型

    高橋俊明, 青木正志, 鈴木直輝, 竪山真規, 早坂美保, 佐藤仁美, 相場瞳, 伊藤真理子, 阿部恵美, 松村剛, 林由起子, 西野一三, 埜中征哉, 今野秀彦, 小野寺宏, 糸山泰人

    日本人類遺伝学会大会プログラム・抄録集　52nd　99　2007

  326. 早期にアキレス腱拘縮をきたしたdistal anterior compartment myopathy

    鈴木直輝, 斎藤浩史, 石黒英明, 廣田紘一, 糸山泰人, 高橋俊明, 青木正志

    日本人類遺伝学会大会プログラム・抄録集　52nd　99　2007

  327. Dislocated neuronal nitric oxide synthase results in muscle atrophy during tail suspension

    N. Suzuki, N. Motohashi, A. Uezumi, S. Fukada, Y. Miyagoe-Suzuki, T. Yoshimura, Y. Itoyama, M. Aoki, S. Takeda

    NEUROMUSCULAR DISORDERS　16　(9-10)　692-693　2006/10

    DOI： 10.1016/j.nmd.2006.05.162 　

    ISSN： 0960-8966

  328. Clinical features of the limb-girdle muscular dystrophy type 2B

    T. Takahashi, M. Aoki, H. Aiba, H. Sato, E. Abe, M. Ito, Y. Onodera, N. Suzuki, M. Tateyama, H. Konno, H. Onodera, Y. Itoyama

    NEUROMUSCULAR DISORDERS　16　(9-10)　696-696　2006/10

    DOI： 10.1016/j.nmd.2006.05.172 　

    ISSN： 0960-8966

  329. マウス尾部懸垂モデルにおけるnNOS/NOを介した筋萎縮の分子機構の解析

    鈴木直輝, 本橋紀夫, 上住聡芳, 深田宗一朗, 鈴木友子, 吉村哲彦, 糸山泰人, 青木正志, 武田伸一

    Inflamm Regen　26　(4)　371　2006/07/01

    ISSN： 1880-9693

  330. 筋疾患の病態と診断,治療戦略の最前線 筋ジストロフィーの再生医療

    上住聡芳, 鈴木直輝, 武田伸一

    小児科診療　69　(4)　570-574　2006/04/01

    Publisher: 診断と治療社

    ISSN： 0386-9806

  331. Dysferlin遺伝子変異の確定した肢帯型筋ジストロフィー(LGMD)2B型の筋障害の分布

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 竪山真規, 今野秀彦, 林由起子, 西野一三, 埜中征哉, 木村格, 糸山泰人

    日本神経学会総会プログラム・抄録集　47th　249　2006

  332. マウス尾部懸垂モデルにおけるnNOS/NOを介した筋萎縮の分子機構の解析

    鈴木直輝, 本橋紀夫, 上住聡芳, 深田宗一朗, 鈴木友子, 武田伸一

    日本神経学会総会プログラム・抄録集　47th　166　2006

  333. MM2型孤発性クロイツフェルト・ヤコブ病の臨床診断

    浜口 毅, 北本 哲之, 佐藤 猛, 水澤 英洋, 中村 好一, 野口 もえ子, 古川 裕, 久慈 一英, 三谷 和子, 村山 繁雄, 郡山 達男, 山下 真理子, 川上 明男, 井原 雄悦, 黒田 重利, 鈴木 直輝, 志賀 裕正, 荒井 啓行, 山田 正仁

    臨床神経学　45　(12)　1162-1162　2005/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  334. 日本人三好型遠位型筋ジストロフィーと肢帯型筋ジストロフィー2B型のジスフェルリン遺伝子変異と臨床経過の比較

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 竪山真規, 相場瞳, 伊藤真理子, 近藤恵美, 松村剛, 林由起子, 西野一三, 埜中征哉, 今野秀彦, 斎藤博, 木村格, 糸山泰人

    国立病院総合医学会　59th　173　2005/10

  335. 後肢懸垂・再荷重モデルにおける筋萎縮・再成長メカニズムの解析

    鈴木直輝, 望月靖史, 上住聡芳, 深田宗一朗, 増田智, 深瀬明子, 鈴木友子, 武田伸一

    炎症・再生　25　(4)　388-388　2005/07/01

    Publisher: (一社)日本炎症・再生医学会

    ISSN： 1346-8022

    eISSN： 1880-5795

  336. A case of staphylococcal sepsis with bacterial maningitis and septicemia

    舛明子, 笹井収, 白鳥宜孝, 佐藤勝久, 鈴木直輝, 加藤昌昭, 塚本哲朗

    臨床皮膚科　59　(7)　613-616　2005/06/01

    Publisher: 医学書院

    DOI： 10.11477/mf.1412101500 　

    ISSN： 0021-4973

  337. 骨髄キメラマウスを用いた後肢懸垂・再荷重モデルにおける筋肥大メカニズムの解析

    鈴木直輝, 望月靖史, 上住聡芳, 深田宗一朗, 増田智, 深瀬明子, 鈴木友子, 武田伸一

    再生医療　4　152　2005/02/10

    ISSN： 1347-7919

  338. MM2型孤発性クロイツフェルト・ヤコブ病の臨床診断

    浜口毅, 久慈一英, 三谷和子, 郡山達男, 山下真理子, 川上明男, 井原雄悦, 鈴木直輝, 荒井啓行

    日本神経学会総会プログラム・抄録集　46th　263　2005

  339. Collected papers of clinical study on treatments and medical administration for muscular dystrophy. Clinical-pathological research on myocardiopathy in Duchenne muscular dystrophy. Research progress in 3 years. 5) Comparison of dysferlin gene mutations an

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 堅山真規, 相場瞳, 伊藤真理子, 近藤恵美, 斎藤博, 木村格, 糸山泰人, 今野秀彦

    筋ジストロフィーの治療と医学的管理に関する臨床研究論文集 平成14-16年度　131-134　2005

  340. Dysferlin遺伝子変異の確定した肢帯型筋ジストロフィー2B型の臨床型の解析

    高橋俊明, 青木正志, 小野寺好明, 鈴木直輝, 今野秀彦, 林由起子, 西野一三, 埜中征哉, 斎藤博

    日本神経学会総会プログラム・抄録集　46th　105　2005

  341. 三好型遠位型と肢帯型筋ジストロフィー2B型のdysferlin遺伝子型と臨床経過

    高橋俊明, 青木正志, 竪山真規, 小野寺好明, 鈴木直輝, 吉岡勝, 今野秀彦, 西野一三, 埜中征哉

    臨床神経学　44　(12)　1160-1160　2004/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  342. Dysferlin遺伝子異常に伴う筋ジストロフィーマウス(SJLマウス)における遺伝子発現解析

    鈴木直輝, 青木正志, 高橋俊明, 日沼雄二, 小野寺好明, 竪山真規, 加藤昌昭, 石垣あや, 割田仁

    臨床神経学　44　(12)　1213-1213　2004/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  343. A patient with distal muscular dystrophy without mutations in dysferlin gene but with abnormal dysferlin localization in muscle fibers

    保住功, 高橋俊明, 青木正志, 林由起子, 鈴木直輝, 松山善次郎, 犬塚貴, 埜中征哉

    臨床神経学　44　(10)　699-702　2004/10

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  344. 遺伝子治療と診療内科 筋ジストロフィーに対する遺伝子治療

    鈴木直輝, 武田伸一

    隔月刊心療内科　8　(4)　237-243　2004/07/28

    ISSN： 1342-9892

  345. Dysferlin遺伝子異常に伴う筋ジストロフィーマウス(SJLマウス)における遺伝子発現解析

    鈴木直輝, 青木正志, 高橋俊明, 日沼雄二, 小野寺好明, 竪山真規, 加藤昌昭, 石垣あや, 割田仁

    日本神経学会総会プログラム・抄録集　45th　371　2004/04/01

  346. 高齢発症で新規遺伝子変異を認めた三好型遠位型筋ジストロフィーの一例

    高野大樹, 鈴木直輝, 青木正志, 高橋俊明, 浅野昌宏, 小野寺好明, 竪山真規, 志賀裕正, 糸山泰人

    臨床神経学　44　(1)　68-68　2004/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  347. MR spectroscopy findings of a case of intravascular malignant lymphoma: Usefulness for differential diagnosis

    Suzuki, N., Nagai, M., Ishigaki, A., Suzuki, Y., Onodera, H., Jokura, E., Kumabe, T., Shiga, Y., Itoyama, Y.

    Clinical Neurology　43　(4)　180-182　2003/04/01

    ISSN： 0009-918X

  348. 細菌性髄膜炎に伴った敗血疹の1例

    舛明子, 笹井収, 白鳥宜孝, 佐藤勝久, 鈴木直輝, 加藤昌昭, 塚本哲朗

    日本皮膚科学会雑誌　113　(1)　71　2003/01/20

    ISSN： 0021-499X

  349. 両側の前骨間神経症候群を呈したneuralgic amyotrophyの1例

    鈴木 直輝, 神 一敬, 志賀 裕正, 加藤 宏之, 糸山 泰人

    脳と神経　54　(7)　605-608　2002/07

    Publisher: (株)医学書院

    ISSN： 0006-8969

  350. A Case of Neuralgic Amyotrophy Manifesting Bilateral Anterior Interosseous Nerve Syndrome.

    鈴木直輝, 神一敬, 志賀裕正, 加藤宏之, 糸山泰人

    Brain Nerve　54　(7)　605-608　2002/07/01

    Publisher: 医学書院

    ISSN： 1881-6096

  351. MR imaging of pyogenic cervical discitis presenting tetraparesis.

    鈴木直輝, 永井真貴子, 鈴木靖士, 志賀裕正, 糸山泰人

    月刊神経内科　56　(3)　295-296　2002/03/25

    ISSN： 0386-9709

Show all ︎Show first 5

Books and Other Publications 8

  1. 筋萎縮性側索硬化症 最新の診療WEB

    鈴木直輝

    2024

  2. 脳神経内科医のための 末梢神経・筋疾患 診断トレーニング「電気生理×病理×画像」を読み解く30ケース 「封入体筋炎」

    鈴木直輝

    南江堂　2019

  3. The Plasticity of Skeletal Muscle.

    Yasuo Kitajima, Naoki Suzuki

    Springer Nature Singapore Ltd　2017

  4. 神経内科Clinical Questions and Pearls 運動ニューロン疾患

    鈴木 直輝

    2017

  5. Neurological Therapeutics

    SUZUKI Naoki

    2015

  6. 骨格筋症候群 新領域別症候群 32

    SUZUKI Naoki

    2015

  7. すべてがわかるALS・運動ニューロン疾患

    SUZUKI Naoki

    2013

  8. 筋疾患診療ハンドブック

    鈴木 直輝

    2013

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Presentations 27

  1. 脳神経内科領域の遺伝学 ～神経筋疾患を中心に～

    鈴木直輝

    遺伝子診療部教育セミナー2023　2023/11/21

  2. GNEミオパチーに対する 経口アセノイラミン酸による治療開発

    鈴木直輝

    第9回日本筋学会学術集会　2023/08/18

  3. Molecular mechanism of motor neuron disease unravelled: achievements from the interdisciplinary collaboration

    Naoki Suzuki

    The 46th Annual Meeting of the Japan Neuroscience Society　2023/08/01

  4. Clinical trials of GNE myopathy in Japan

    Naoki Suzuki

    64th Annual Meeting of the Japanese Society of Neurology　2023/06/02

  5. Advanced Medicine for ALS

    Naoki Suzuki

    64th Annual Meeting of the Japanese Society of Neurology　2023/06/01

  6. 封入体筋炎の病態の理解と治療開発 Invited

    日本筋学会　2022/08/05

  7. 運動ニューロンオルガノイド培養を用いた筋萎縮性側索硬化症の病態解明 Invited

    鈴木直輝

    Neuro2022　2022/06/30

  8. 細胞膜修復異常と異常蛋白凝集を呈する筋疾患の病態・治療研究 Invited

    鈴木直輝

    第76回日本体力医学会大会　2021/09/17

  9. ヒトiPS細胞由来神経オルガノイドを用いた筋萎縮性側索硬化症の軸索病態の解析 Invited

    鈴木直輝

    東海大学卓越研究員シンポジウム 「ヒト多能性幹細胞と多層的トランスレーショナル研究」　2020/12/07

  10. 筋萎縮性側索硬化症（ALS）の軸索構造に注目した病態解析 Invited

    鈴木直輝

    電気化学会東北支部 第33回東北若手の会　2020/12/05

  11. ALSのiPS細胞モデルの有⽤性と特性 Invited

    鈴木直輝

    第61回日本神経学会　2020/08/31

  12. 筋萎縮性側索硬化症（ALS）の治療開発 Invited

    鈴木 直輝

    メタルバイオサイエンス2018　2018/11/16

  13. Substantial axonal degeneration has occurred before motor neuron loss in ALS models

    SUZUKI Naoki

    59th Annual Meeting of the Japanese Society of Neurology　2018/05/26

  14. 齧歯類モデルを基盤としたALSの治療開発：HGFを中心に Invited

    鈴木 直輝

    第35回日本神経治療学会　2017/11

  15. GNEミオパチーに対するシアル 酸補充による医師主導治験 Invited

    鈴木 直輝

    第3回 日本筋学会　2017/08

  16. マイクロ流体デバイスを用いた運動ニューロンの軸索病態の解析 Invited

    鈴木 直輝

    第69回日本細胞生物学会大会　2017/06

  17. Proteasomal proteolysis is indispensable for the maintenance of skeletal muscle and muscle stem cells International-presentation

    SUZUKI Naoki

    21th World Muscle Society　2016/10

  18. Genetic profile for suspected dysferlinopathy identified by targeted next generation sequencing International-presentation

    SUZUKI Naoki

    13th International Congress of Human Genetics　2016/04

  19. Regenerative therapies for ALS using hepatocyte growth factor International-presentation

    SUZUKI Naoki

    rd World Centenarian Intiative International Symposium　2016

  20. Neurogenesis and Synaptogenesis Using Human Pluripotent Stem Cells International-presentation

    MAROOF Asif, SUZUKI Naoki

    12th International Society for Stem Cell Research Modeling　2014/06

  21. Expression pattern of the C9ORF72 mouse ortholog corresponds with the selectivity of neural degeneration in ALS / FTD International-presentation

    SUZUKI Naoki

    Neuroscience 2013　2013/11

  22. Expression pattern of C9ORF72 ortholog in mice International-presentation

    SUZUKI Naoki

    65th American Academy of Neurology　2013/03

  23. Expression pattern of C9orf72 ortholog in mice International-presentation

    SUZUKI Naoki

    8th ALS symposium de la Fondation André-Delambre　2012/09

  24. Prevalence of inclusion body myositis (IBM) in Japanese population International-presentation

    SUZUKI Naoki

    15th World Muscle Society　2010/10

  25. Prevalence of inclusion body myositis (IBM) in Japanese population International-presentation

    SUZUKI Naoki

    12th International Congress on Neuromuscular Diseases　2010/07

  26. The increasing Number of Inclusion Body Myositis (IBM) in Japan International-presentation Invited

    SUZUKI Naoki

    9th Asian and Oceanian Myology Center (AOMC) Meeting　2010/03

  27. Dislocation of neuronal nitric oxide synthase contributes to muscle atrophy in amyotrophic lateral sclerosis International-presentation

    SUZUKI Naoki

    13th World Muscle Society　2008/10

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Industrial Property Rights 4

  1. ユートロフィン遺伝子発現増強物質のスクリーニング

    武田 伸一, 谷端 淳, 鈴木 直輝, 鈴木 友子

    Property Type: Patent

  2. ユートロフィン遺伝子発現増強物質のスクリーニング

    武田 伸一, 谷端 淳, 鈴木 直輝, 鈴木 友子

    特許第5250810号

    Property Type: Patent

  3. 神経軸索分岐異常の改善剤

    Property Type: Patent

  4. 細胞膜の損傷修復促進剤

    Property Type: Patent

Research Projects 22

  1. Contribution of post-proteolytic pathways to skeletal muscle volume

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2024/04/01 - 2027/03/31

  2. Elucidation of the molecular pathogenesis of ALS using a motor neuron-skeletal muscle cell model

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  3. Elucidation of the molecular pathogenesis of ALS using a motor neuron-skeletal muscle cell model

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  4. Aberrant RNA splicing in sporadic inclusion body myositis

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2023/06/30 - 2025/03/31

  5. The role of post-proteolytic aminopeptidases in skeletal muscle homeostasis

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2021/04/05 - 2024/03/31

  6. 筋萎縮性側索硬化症モデルにおける軸索分岐異常の分子基盤の解明

    鈴木 直輝, 割田 仁, 青木 正志

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(C)

    Category: 基盤研究(C)

    Institution: 東北大学

    2021/04/01 - 2024/03/31

    More details Close

    筋萎縮性側索硬化症(ALS)は運動ニューロンが系統的に障害され根本的な治療が未だ無い難病である。ALSの多くを占める孤発性ALSの剖検脳・脊髄ではTDP-43の封入体が見られる。TDP-43をコードするTARDBPはFUSやhnRNPA1と共に家族性ALSの原因遺伝子であり、またRNA結合蛋白でもある。RNA代謝異常は、軸索障害とともに家族性・孤発性ALSに共通して見られる病態機序である。独自開発したマイクロ流体デバイスを用いiPS細胞由来運動ニューロン軸索を大量に回収・網羅的解析し、FUS、hnRNPA1、TDP-43といった代表的なRNA結合蛋白変異における病態を比較解析してきた。 本年度はRNA-seq解析により、TARDBP変異による軸索局所でのRNA代謝異常を転写レベルで解析した。PHOX2Bを見出し、その発現抑制で健常者運動ニューロンの突起伸長抑制が再現された。動物モデルとして、ゼブラフィッシュでも、モルフォリノによるPHOX2Bの発現抑制実験で、細胞モデルと同様に脊髄軸索長が低下し、さらに運動機能も低下した。PHOX2Bは、ALSで発症後長期まで保たれる動眼神経や自律神経において発現が高いことから、変異運動ニューロンの選択的変性に関わる可能性が考えられる。上記の新しい知見をStem Cell Reports誌に報告した（Mitsuzawa S, et al. Stem Cell Reports 2021）。各遺伝子変異の共通分子の解析や動物モデルを用いた検証を行っていく。

  7. ALS共通病態としての軸索変性と軸索再生：細胞種選択的な治療法開発

    青木 正志, 割田 仁, 鈴木 直輝

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 基盤研究(B)

    Category: 基盤研究(B)

    Institution: 東北大学

    2020/04/01 - 2023/03/31

  8. Elucidation of the pathogenesis of inclusion body myositis by focusing on the abnormal aggregation protein clearance system

    AOKI Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: Tohoku University

    2020/07/30 - 2022/03/31

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    Inclusion body myositis (sIBM) is a chronic, progressive and refractory muscle disease seen in middle-aged and older people. sIBM patients' skeletal muscles show abnormal aggregates such as amyloid-beta, TDP-43 and FUS, suggesting a degenerative disease in the muscle. Using an originally developed human skeletal muscle electrical pulse culture system, we found cytoplasmic deposition of TDP-43, one of the aggregation proteins found in ALS. The results were reported in SciRep journal. Myoblasts were established from three new cases of sIBM muscle biopsies. B-cell follicle in sIBM muscle tissue were also observed in a case. It was summarised and reported in NeuromusDisord journal.

  9. Contribution of protein recycling system for the maintenance of skeletal muscle mass

    Nagatomi Ryoichi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2018/04/01 - 2021/03/31

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    Proteolysis has long been considered deleterious to skeletal muscle. Recent studies, however, have identified that impaired proteolytic function leads to loss instead of an increase in skeletal muscle mass. Dysfunction in the proteasome-dependent proteolytic pathway in skeletal muscle induced more significant loss or impaired development than dysfunction in the autophagy pathway. Although we failed to detect the recycling of degradation derived amino acids for de-novo protein synthesis, we found the induction of various aminopeptidases linked to the proteasome-dependent proteolytic pathway. Each aminopeptidase in cultured myoblasts demonstrated essential roles, such as the regulations of ATP concentration, cell cycle and initiation of differentiation, and determination of polarity and structure of myotubes. Although further studies are required to elucidate the underlying mechanisms, we could demonstrate the essential roles of post-proteolytic aminopeptidases in developing myoblasts.

  10. Analysis of axonal pathomechanism in amyotrophic lateral sclerosis using human iPS cell-derived nerve organoid.

    Suzuki Naoki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2018/04/01 - 2021/03/31

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    RNA sequencing analysis of axonal fraction of nerve organoid revealed a gene, Fos-B, associated with the pathogenesis of FUS mutations. We demonstrated that Fos-B is involved in the formation of abnormal axon branching associated with FUS mutations in motor neurons using overexpression and inhibition experiments. Furthermore, using zebrafish overexpression of Fos-B and human autopsy spinal cord, we clarified the relationship between Fos-B and ALS pathology. These results were reported in EBioMedicine in 2019. We wrote a review on omics analysis of axons, which was published in Frontiers in Neuroscience in 2020. In 2021, we found decreased expression of Phox2B using TARDBP mutant iPS cells, the causative gene of ALS, and it was accepted by Stem Cell Reports. We will continue to investigate the axonal pathology underlying motor neuron vulnerability.

  11. ヒトiPS細胞由来神経オルガノイドを用いた筋萎縮性側索硬化症の軸索病態の解析 Competitive

    鈴木 直輝

    Offer Organization: 文部科学省

    System: 科学研究費補助金（基盤研究(C)）

    2018/04 - 2021/03

  12. Elucidating the mechanism of abnormal protein aggregation in sporadic inclusion body myositis by single molecule nanoimaging

    Aoki Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Challenging Research (Exploratory)

    Category: Challenging Research (Exploratory)

    Institution: Tohoku University

    2018/06/29 - 2020/03/31

    More details Close

    In this study, myoblasts were harvested from sporadic inclusion body myositis (sIBM) patients during muscle biopsy, and a total of six lines were stocked during these two years. Cellular stress was applied to human skeletal muscle using electro-pulse-constriction-culture-system (EPS) which reproduces long-lasting muscle contraction. Analysis was performed by RNA sequencing using cells before and after contraction stress. The characteristics of the co-culture system (EPS culture) were reported in an international journal. In addition, TDP-43, which is a component of the aggregates, is labeled by single-molecule nanoimaging, and the presence or absence of aggregate formation before and after EPS culture was evaluated. Furthermore, analysis of the myoblast specific proteasome deficient mouse revealed that p53 is important for the maintenance of myoblasts pool.

  13. Unraveling common mechanisms underlying neuromuscular degeneration in multisystem proteinopathy

    Aoki Masashi, OKANO HIDEYUKI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2016/04/01 - 2019/03/31

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    Multisystem proteinopathy (MSP) is an inherited neuromuscular syndrome characterized by progressive and selective degeneration of skeletal muscle, bone, cerebrocortical, and motor neuron with aberrant protein aggregates, resulting in a combination of amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy (IBM), and Paget disease of bone. In this study, using patient-derived induced pluripotent stem cells (iPSCs), we have developled motor neurons and skeletal muscle cells with an MSP type 3 (MSP3)-linked hnRNPA1 gene mutation. Isogenic control iPSCs are also under development. To reveal the underlying pathomechanisms particularly related to assembly/disassembly of RNA granules, we are trying to recapitulate pathological phenotypes in these human cellular models of MSP3.

  14. 遠位型ミオパチーにおける承認申請に向けたアセノイラミン酸の長期投与試験

    Offer Organization: 日本医療研究開発機構 AMED

    System: 希少難治性疾患に対する画期的な医薬品医療機器等の実用化に関する研究（［新規化合物等治験］（ステップ２））

    2018 - 2019

  15. Elucidating the molecular pathology of inclusion body myositis using novel culture system and next generation sequencer

    Aoki Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

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    As for sIBM, patient samples were collected and clinical information was also collected at the same time. The significance of autoantibody pathology in patient serum was analyzed by human serum and mouse experiment in collaboration with Kumamoto University. CD56 positive skeletal myoblasts from some skeletal muscles were collected and established from 8 sIBM cases. RNA sequencing was performed on 4 cases of sIBM. Including comparison with 9 hereditary inclusive body myopathies, disease-related reported mutations and rare variants were extracted. We are also analyzing mice model based on proteasome dysfunction hypothesis.

  16. Elucidating cell type-specific pathology of ALS using isogenic iPS cells Competitive

    Suzuki Naoki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)

    Category: Grant-in-Aid for Young Scientists (A)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

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    FUS gene mutation in 13 families was identified by accumulation of familial ALS families. Among them, skin biopsy of FUS-related ALS (FUS-ALS) in two families was carried out with consent in accordance with the procedure approved by the Ethics Committee of the University. From this, primary culture fibroblasts were established and iPS cells were established at a collaborating researcher's facility. We analyzed RNA sequence sequence after motor neuron differentiation and reported to Stem Cell Reports in 2016. We also produced isogenic lines using genome editing technology. In order to reproduce the characteristic long axon protrusions of motor neurons in the culture environment using the iPS cells produced, we also examined the condition in a novel microfluidic device. By RNAseq analysis, gene profiles expressed in cell bodies and axons were identified.

  17. Genetic analysis and establishment of in vitro model for inclusion body myositis

    Aoki Masashi, Kato MASAAKI, SUZUKI Naoki, WARITA Hitoshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown etiology and without effective treatment. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers and rimmed vacuoles, suggesting inflammation and degeneration co-exist as part of the pathomechanism. We made muscle specific proteasomal deficient mice and reported in JCS paper. We also found familial case of inclusion body myopathy with the mutation in hnRNPA1. We also established iPS cells from these patients.

  18. Elucidating the RNA pathomechanism in FUS-FALS iPS induced motor neurons

    Aoki Masashi, Kato MASAAKI, Naoki SUZUKI, Hitoshi WARITA, OKANO Hideyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2013/04/01 - 2016/03/31

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    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in the selective death of motor neurons. ALS symptoms are associated with muscle weakness and paralysis and approximately 80% of ALS patients die within 5 years after the onset of these symptoms. We generated induced pluripotent stem cells (iPSC) from familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability (Ichiyanagi et al. Stem Cell Reports 2016).

  19. iPS細胞を用いた家族性ALSの病態解明・新規治療法開発

    Offer Organization: 日本医療研究開発機構 AMED

    System: 疾患特異的iPS細胞を用いた難治性疾患の病態解明及び治療法開発に関する研究

    2015 - 2016

  20. FUS変異を持つ筋萎縮性側索硬化症の大家系における剖検病理を基盤とした病態解析 Competitive

    鈴木 直輝

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業 若手研究(B)

    Category: 若手研究(B)

    Institution: 東北大学

    2010 - 2011

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    筋萎縮性側索硬化症(ALS)は原因不明で治療法が無い難病である。近年Fused in Sarcoma(FUS)遺伝子異常を持つ家族性ALSが報告され、当科の家族性ALS症例でもFUS異常を3家系で見出した。自験例の大家系は5剖検例を含み、それら剖検例における細胞内封入体を含めた詳細な臨床病理学的解析は運動ニューロン病全体の病態解明に重要な意義を持つ。FUS変異が運動ニューロン死を引き起こすメカニズムは明らかになっていない。本研究では、自験の大家系について各症例の臨床像を検査・画像所見を含めてより詳細に明らかにし、臨床経過を完全に把握する。剖検病理標本を詳細に検討することで好塩基性封入体の分布や頻度、病期との相関について検討する。さらに凍結保存された脳・脊髄を用いての解析も可能である。具体的にはFUSのRNA代謝という機能面に注目してFUS異常ALS患者のR521C異常を持つ大家系を含めた発症者全員に関する臨床情報を解析し遺伝子異常を持つ患者の特徴をより一層明らかにする。 平成22年度はFUS異常ALS患者の脳・脊髄病理標本を対象とし、特に好塩基性封入体の病態・病期との関わりに注目し封入体の分布や頻度を解析し病態における意義を明らかにした。形態学的解析に加えてTDP-43やFUSを用いた免疫組織化学的検討も行った。発症後1,3,9年目の剖検例では病初期には脊髄に加え黒質の変性が強く、病期を追うごとに変性・封入体の存在領域の拡大を認めた。平成23年度は免疫染色での検討も加え、同一家系における病態の進行について論文にまとめ、投稿した。

  21. Elucidate the pathomechanism of inclusion body myositis(IBM) Competitive

    ITOYAMA Yasuto, AOKI Masashi, SUZUKI Naoki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: National Center of Neurology and Psychiatry

    2010 - 2011

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    Sporadic inclusion body myositis(sIBM) is an intractable and progressive skeletal muscle disease of unknown cause and without effective treatment. Our purpose is to elucidate the pathomechanism of sIBM exploring the autoantibody in the serum of sIBM patients using protein array. We also produced muscle specific proteasome deficient mice as the disease model of sIBM.

  22. Targeting neuronal nitric oxide synthase as a therapy for muscle atrophy in amyotrophic lateral sclerosis Competitive

    SUZUKI Naoki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (Start-up)

    Category: Grant-in-Aid for Young Scientists (Start-up)

    Institution: Tohoku University

    2007 - 2008

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Teaching Experience 2

  1. Rehabilitation

  2. Neurology

Academic Activities 1

  1. 封入体筋炎 診療の手引き

    Activity type: Academic research