Muscle-dominant wild-type TDP-43 transgenic mice as a novel model of sporadic inclusion body myositis

• Project/Area Number: 16K09674
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kumamoto University
• Principal Investigator: YAMASHITA Satoshi 熊本大学, 大学院生命科学研究部(医), 准教授 (20457592)
• Research Collaborator: ANDO yukio ; TAKEDA naoki ; TAWARA nozomu ; DOKI tsukasa ; MATSUO yoshimasa
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 封入体筋炎 / TDP-43 / Tubular aggregate / NT5C1A / ミトコンドリア / 小胞体ストレス / IL-6 / 脳神経疾患 / 神経科学

Outline of Final Research Achievements

Muscle histology of inclusion body myositis (IBM) demonstrates inflammatory findings and degenerative features including accumulation of TDP-43. However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in IBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter. The mice showed increased serum levels of myogenic enzymes. Muscle histology demonstrated myopathic changes including fiber size variation, abundant tubular aggregates, and TDP-43 aggregation. Proteomic analysis identified increased SR/ ER-resident proteins as well as cytosolic 5'-nucleotidase 1A. Muscle-dominant wild-type TDP-43 expression indeed caused myotoxicity featuring tubular aggregates and TDP-43-positive inclusions.

Academic Significance and Societal Importance of the Research Achievements

封入体筋炎（IBM）は高齢者に好発する筋疾患であり、加齢に伴って起こる筋症＝サルコぺニアのモデルとなる点でも今後注目すべき疾患である。本疾患の骨格筋では、筋萎縮性側索硬化症などの神経変性疾患に共通してTDP-43が沈着しており、TDP-43プロテイノパチーの一型でもある。本マウスを用いて、TDP-43の筋線維内凝集を抑制する低分子化合物スクリーニングシステムを構築し、IBMの根治的治療法を探索することは、高齢者の運動機能を著しく低下させるサルコぺニアやALSなどの神経変性疾患の治療法開発に展開可能であると期待される。

Research Products

• [Int'l Joint Research] Washington University(米国)
• [Journal Article] Assessment of oropharyngeal swallowing dysfunction in myasthenia gravis patients presenting with difficulty in swallowing (2019)
  • Author(s): Kumai Yoshihiko、Miyamoto Takumi、Matsubara Keigo、Samejima Yasuhiro、Yamashita Satoshi、Ando Yukio、Orita Yorihisa
  • Journal Title: Auris Nasus Larynx Volume: 46 Issue: 3 Pages: 390-396
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• [Journal Article] Impact of major earthquakes on Parkinson’s disease (2019)
  • Author(s): Kurisaki Ryoichi、Ueyama Hidetsugu、Maeda Yasushi、Sakamoto Tetsuro、Nakahara Keiichi、Nakane Shunya、Yamashita Satoshi、Ando Yukio
  • Journal Title: Journal of Clinical Neuroscience Volume: 61 Pages: 130-135
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• [Journal Article] Mitochondrial localization of PABPN1 in oculopharyngeal muscular dystrophy. (2019)
  • Author(s): Tsukasa Doki, Satoshi Yamashita, Fan-Yan Wei, Kentaro Hara, Takahiro Yamamoto, Ziwei Zhang, Xiao Zhang, Nozomu Tawara, Hirotake Hino, Eiichiro Uyama, Takashi Kurashige, Hirofumi Maruyama, Kazuhito Tomizawa, Yukio Ando.
  • Journal Title: Laboratory Investigation Volume: 印刷中 Issue: 11 Pages: 1728-1740
  • DOI: 10.1038/s41374-019-0243-8
  • Peer Reviewed / Open Access
• [Journal Article] 増大特集 Antibody Update 2018 封入体筋炎と自己抗体 (2018)
  • Author(s): 山下 賢、安東 由喜雄
  • Journal Title: BRAIN and NERVE Volume: 70 Issue: 4 Pages: 449-457
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  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2018-04-01
• [Journal Article] Muscle-dominant wild-type TDP-43 expression induces myopathological changes featuring tubular aggregates and TDP-43-positive inclusions (2018)
  • Author(s): Tawara Nozomu、Yamashita Satoshi、Kawakami Kensuke、Kurashige Takashi、Zhang Ziwei、Tasaki Masayoshi、Yamamoto Yasuhiro、Nishikami Tomo、Doki Tsukasa、Zhang Xiao、Matsuo Yoshimasa、Kimura En、Tawara Akie、Maeda Yasushi、Hauschka Stephen D.、Maruyama Hirofumi、Ando Yukio
  • Journal Title: Experimental Neurology Volume: 309 Pages: 169-180
  • DOI: 10.1016/j.expneurol.2018.08.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis (2018)
  • Author(s): Okada Masamitsu、Yamashita Satoshi、Ueyama Hidetsugu、Ishizaki Masatoshi、Maeda Yasushi、Ando Yukio
  • Journal Title: eNeurologicalSci Volume: 11 Pages: 11-14
  • DOI: 10.1016/j.ensci.2018.05.001
  • Peer Reviewed / Open Access
• [Journal Article] Tongue strength in patients with subacute myelo-optico-neuropathy (2018)
  • Author(s): Yamashita Satoshi、Nakama Tatsuya、Ueda Mitsuharu、Honda Shoji、Kimura En、Konagaya Masaaki、Ando Yukio
  • Journal Title: Journal of Clinical Neuroscience Volume: 47 Pages: 84-88
  • DOI: 10.1016/j.jocn.2017.10.007
  • Peer Reviewed
• [Journal Article] Cerebrotendinous xanthomatosis presenting with extensive cerebral cortex symptoms: A case report (2018)
  • Author(s): Mukaino Akihiro、Tsuda Mayumi、Yamashita Satoshi、Kosaka Takayuki、Wada Kuniyasu、Ando Yukio
  • Journal Title: Clinical Neurology and Neurosurgery Volume: 174 Pages: 217-219
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• [Journal Article] Determination of cN1A Autoantibodies by Cell-Based Immunofluorescence Cytochemistry (2018)
  • Author(s): Yamashita Satoshi、Tawara Nozomu
  • Journal Title: Methods Mol. Biol. Volume: - Pages: 89-94
  • DOI: 10.1007/978-1-4939-8949-2_7
  • ISBN: 9781493989485, 9781493989492
  • Peer Reviewed
• [Journal Article] Utility of skinfold thickness measurement in non-ambulatory patients with Duchenne muscular dystrophy. (2017)
  • Author(s): Ishizaki M, Kedoin C, Ueyama H, Maeda Y, Yamashita S, Ando Y.
  • Journal Title: Neuromuscul Disord. Volume: 27 Issue: 1 Pages: 24-28
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• [Journal Article] Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients. (2017)
  • Author(s): Nakahara K, Nakane S, Nakajima M, Yamashita S, Mori T, Ando Y.
  • Journal Title: J Neuroimmunol Volume: 305 Pages: 182-185
  • DOI: 10.1016/j.jneuroim.2017.01.005
  • Peer Reviewed
• [Journal Article] Pathomechanisms of anti-cytosolic 5'-nucleotidase 1A autoantibodies in sporadic inclusion body myositis. (2017)
  • Author(s): Tawara N, Yamashita S, Zhang X, Korogi M, Zhang Z, Doki T, Matsuo Y, Nakane S, Maeda Y, Sugie K, Suzuki N, Aoki M, Ando Y.
  • Journal Title: Ann Neurol. Volume: 81 Issue: 4 Pages: 512-525
  • DOI: 10.1002/ana.24919
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hemiatrophy of the Tongue with Contralateral Hemiparesis in a Patient with Multifocal Acquired Demyelinating Sensory and Motor Neuropathy (2017)
  • Author(s): Ikenoshita Susumu、Yamashita Satoshi、Sakamoto Tetsuro、Misumi Yohei、Ando Yukio
  • Journal Title: Journal of Clinical Neurology Volume: 13 Issue: 4 Pages: 422-422
  • DOI: 10.3988/jcn.2017.13.4.422
  • Peer Reviewed
• [Journal Article] Anti-NT5C1A autoantibodies for the diagnosis and study of the pathogenesis of sporadic inclusion body myositis (2017)
  • Author(s): Yamashita Satoshi、Tawara Nozomu、Ando Yukio
  • Journal Title: Clinical and Experimental Neuroimmunology Volume: 8 Issue: 4 Pages: 292-301
  • DOI: 10.1111/cen3.12420
  • Peer Reviewed
• [Journal Article] Multicenter questionnaire survey for sporadic inclusion body myositis in Japan. (2016)
  • Author(s): Suzuki N, Mori-Yoshimura M, Yamashita S, Nakano S, Murata KY, Inamori Y, Matsui N, Kimura E, Kusaka H, Kondo T, Higuchi I, Kaji R, Tateyama M, Izumi R, Ono H, Kato M, Warita H, Takahashi T, Nishino I, Aoki M.
  • Journal Title: Orphanet J Rare Dis. Volume: 11 Issue: 1 Pages: 146-146
  • DOI: 10.1186/s13023-016-0524-x
  • NAID: 120006937646
  • Peer Reviewed / Open Access
• [Journal Article] Thomsen disease associated with ptosis and abnormal MR findings (2016)
  • Author(s): Mori Y, Yamashita S, Kato M, Masuda T, Takamatsu K, Kumamoto T, Sasaki R, Ando Y
  • Journal Title: Neuromuscl Disord Volume: 26 Issue: 11 Pages: 805-808
  • DOI: 10.1016/j.nmd.2016.08.016
  • Peer Reviewed
• [Journal Article] Hereditary amyloidosis with cardiomyopathy caused by the novel variant transthyretin A36D. (2016)
  • Author(s): Yamashita T, Ueda M, Saga N, Nanto K, Tasaki M, Masuda T, Misumi Y, Oda S, Fujimoto A, Amano T, Takamatsu K, Yamashita S, Obayashi K, Matsui H, Ando Y.
  • Journal Title: Amyloid Volume: in press Issue: 3 Pages: 207-208
  • DOI: 10.1080/13506129.2016.1202228
  • Peer Reviewed
• [Journal Article] Lateral asymmetry and spatial difference of iron deposition in the substantia nigra of patients with Parkinson disease measured with quantitative susceptibility mapping (2016)
  • Author(s): Azuma M, Hirai T, Yamada K, Yamashita S, Ando Y, Tateishi M, Iryo Y, Yoneda T, Kitasima M, Wang Y, Yamashita Y
  • Journal Title: Am. J. Neuroradiol Volume: 0 Issue: 5 Pages: 1-7
  • DOI: 10.3174/ajnr.a4645
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation. (2016)
  • Author(s): Okumura K, Yamashita T, Masuda T, Misumi Y, Ueda A, Ueda M, Obayashi K, Jono H, Yamashita S, Inomata Y, Ando Y.
  • Journal Title: Amyloid Volume: 23 Issue: 1 Pages: 39-45
  • DOI: 10.3109/13506129.2015.1123149
  • Peer Reviewed
• [Journal Article] CMAP decrement as a potential diagnostic marker for ALS. (2016)
  • Author(s): Mori A, Yamashita S, Nakajima M, Hori H, Tawara A, Matsuo Y, Misumi Y, Ando Y.
  • Journal Title: Acta Neurol Scand. Volume: 134 Issue: 1 Pages: 49-53
  • DOI: 10.1111/ane.12510
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Clinical differences between sporadic inclusion body myositis with and without intramuscular amyloid-like deposits. (2018)
  • Author(s): Yamashita S., Ikeda T., Tawara N., Zhang X., Doki T., Matsuo Y., Zhang Z., Hara K., Ando Y.
  • Organizer: The XVI International Symposium on Amyloidosis
  • Int'l Joint Research
• [Presentation] Intramyofiber amyloid deposits of transgenic mice overexpressing mutant Matrin 3 are involved in the pathogenesis of Vocal Cord Pharyngeal Distal Myopathy. (2018)
  • Author(s): Hara K., Yamashita S., Zhang X., Tawara N., Doki T., Zhang Z., Matsuo Y., Nagai M., Ando Y.
  • Organizer: The XVI International Symposium on Amyloidosis
  • Int'l Joint Research
• [Presentation] 封入体筋炎 (2018)
  • Author(s): 山下 賢
  • Organizer: 第59回日本神経学会総会
  • Invited
• [Presentation] Clinical characteristics of sporadic inclusion body myositis with anti-NT5C1A antibodies. (2018)
  • Author(s): Yamashita S., Tawara N., Ikeda T., Zhang X., Doki T., Matsuo Y., Zhang Z., Hara K., Ando Y.
  • Organizer: 第59回日本神経学会総会
• [Presentation] Generation of novel active immunization model of sporadic inclusion body myositis. (2018)
  • Author(s): Tawara N., Yamashita S., Zhang Z., Zhang X., Hara K., Doki T., Matsuo Y., Nakane S., Ando Y.
  • Organizer: 第59回日本神経学会総会
• [Presentation] Overexpression of mutant MATR3 recapitulates clinicopathological features of VCPDM and ALS in mice. (2018)
  • Author(s): Zhang X., Yamashita S., Tawara N., Doki T., Hara K., Zhang Z., Ando Y.
  • Organizer: 第59回日本神経学会総会
• [Presentation] Similarity of pathological features between patients with VCPDM and mice injected with AAV vectors. (2018)
  • Author(s): Hara K., Zhang X., Yamashita S., Tawara N., Doki T., Zhang Z., Ando Y.
  • Organizer: 第59回日本神経学会総会
• [Presentation] The relationship between myofiber necrosis and CD59 levels in immune mediated necrotizing myopathy. (2018)
  • Author(s): Zhang Z., Yamashita S., Tawara N., Doki T., Zhang X., Hara K., Ando Y.
  • Organizer: 第59回日本神経学会総会
• [Presentation] Dysregulation of CYLD is involved in the pathogenesis of sporadic inclusion body myositis. (2017)
  • Author(s): Yamashita S, et al
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Predominant atrophy in type 2 myofibers of sporadic inclusion body myositis with anti-cN1A autoantibody. (2017)
  • Author(s): Tawara N, Yamashita S, et al
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] CYLD is a possible therapeutic target for sporadic inclusion body myositis. (2017)
  • Author(s): Yamashita S, et al
  • Organizer: 22nd International Congress of the World Muscle Society
  • Int'l Joint Research
• [Presentation] Establishment of novel autoimmune animal model for sporadic inclusion body myositis. (2017)
  • Author(s): Tawara N, Yamashita S, et al
  • Organizer: 22nd International Congress of the World Muscle Society
  • Int'l Joint Research
• [Presentation] Mitochondrial analysis in wild-type TDP-43 transgenic mice mimicking sporadic inclusion body myositis. (2017)
  • Author(s): Zhang Z, Yamashita S, et al
  • Organizer: 22nd International Congress of the World Muscle Society
  • Int'l Joint Research
• [Presentation] Endoplasmic reticulum stress in the pathogenesis of a murine model and patients of inclusion body myositis. (2016)
  • Author(s): Satoshi Yamashita, Nozomu Tawara, Tsukasa Doki, Xiao Zhang, Ziwei Zhang, Yoshimasa Matsuo, Yasuhiro Yonemochi, Yukio Ando.
  • Organizer: 21st International Congress of the World Muscle Society
  • Place of Presentation: Congress Palace, Granada, Spain
  • Year and Date: 2016-10-06
  • Int'l Joint Research
• [Presentation] Effect of anti-Cytosolic 5’-nucleotidase 1A (NT5C1A) antibody on cultured muscle cells and muscle fibers of mice. (2016)
  • Author(s): Nozomu Tawara, Satoshi Yamashita, Mai Korogi, Xiao Zhang, Tsukasa Doki, Shunya Nakane, Yasushi Maeda, Yukio Ando.
  • Organizer: 21st International Congress of the World Muscle Society
  • Place of Presentation: Congress Palace, Granada, Spain
  • Year and Date: 2016-10-06
  • Int'l Joint Research
• [Presentation] Establishment of a murine model of vocal cord and pharyngeal weakness with distal myopathy. (2016)
  • Author(s): Xiao Zhang, Satoshi Yamashita, Nozomu Tawara, Tsukasa Doki, Ziwei Zhang, Yoshimasa Matsuo, Yasuhiro Yonemochi, Yukio Ando.
  • Organizer: 21st International Congress of the World Muscle Society
  • Place of Presentation: Congress Palace, Granada, Spain
  • Year and Date: 2016-10-06
  • Int'l Joint Research
• [Presentation] Mitochondrial dysfunction in the pathogenesis of oculopharyngeal muscular dystrophy. (2016)
  • Author(s): Tsukasa Doki, Satoshi Yamashita, Ziwei Zhang, Xiao Zhang, Nozomu Tawara, Yasushi Maeda, Hirotake Hino, Eiichiro Uyama, Kimi Araki, Yukio Ando.
  • Organizer: 21st International Congress of the World Muscle Society
  • Place of Presentation: Congress Palace, Granada, Spain
  • Year and Date: 2016-10-05
  • Int'l Joint Research
• [Presentation] 運動ニューロン疾患の診断と鑑別疾患 (2016)
  • Author(s): 山下 賢
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-21
  • Invited
• [Presentation] 呼吸不全をきたしたALSにおけるより安全な胃瘻造設術の検討 (2016)
  • Author(s): 長尾麻子、石崎雅俊、山下哲司、奥村幸祐、岡崎敏郎、前田 寧、上山秀嗣、川田康誠、山下 賢、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-21
• [Presentation] 筋萎縮性側索硬化症患者の医療処置法の選択に影響を及ぼす要因についての検討 (2016)
  • Author(s): 天野朋子、山下 賢、高松孝太郎、三隅洋平、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-21
• [Presentation] 高齢発症抗AQP4抗体陽性視神経脊髄炎関連疾患の臨床的特徴の解明 (2016)
  • Author(s): 山川詩織、山下 賢、高松孝太郎、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-21
• [Presentation] Endoplasmic reticulum stress in murine model and patients with inclusion body myositis. (2016)
  • Author(s): Satoshi Yamashita, Nozomu Tawara, Tsukasa Doki, Yoshimasa Matsuo, Yasuhiro Yonemochi, Yukio Ando.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-20
• [Presentation] 孤発性封入体筋炎における抗NT5C1A抗体の病態におよぼす影響 (2016)
  • Author(s): 俵 望、山下 賢、興梠 舞、松尾淳一、張 霄、道鬼つかさ、松尾圭将、中根俊成、前田 寧、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-20
• [Presentation] 抗NT5C1A抗体の筋毒性 (2016)
  • Author(s): 興梠 舞、俵 望、山下 賢、中根俊成、松尾淳一、張 霄、道鬼つかさ、松尾圭将、前田 寧、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-20
• [Presentation] 入院時歩行不能状態にあったHTLV-I関連脊髄症の臨床的検討 (2016)
  • Author(s): 原健太朗、山下 賢、増田曜章、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-20
• [Presentation] VCPDMモデルマウスの作成および筋病理学的解析 (2016)
  • Author(s): 張 霄、山下 賢、松尾淳一、松尾圭将、道鬼つかさ、興梠 舞、俵 望、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] 重症筋無力症の抗AChR抗体価と胸腺病理所見、胸腺摘出術の有効性との関連 (2016)
  • Author(s): 中原圭一、中根俊成、高松孝太郎、中島 誠、山下 賢、森 毅、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] 眼咽頭筋ジストロフィーにおけるミトコンドリア障害の解析 (2016)
  • Author(s): 道鬼つかさ、山下 賢、松尾圭将、俵 望、日野洋健、前田 寧、宇山英一郎、荒木喜美、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] 声帯および咽頭麻痺を伴う遠位型ミオパチー（VCPDM）の筋病理学的解析 (2016)
  • Author(s): 松尾淳一、山下 賢、張 霄、松尾圭将、道鬼つかさ、俵 望、安東由喜雄.
  • Organizer: 第57回日本神経学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Book] 神経内科Clinical Questions & Pearls 運動ニューロン疾患 (2017)
  • Author(s): 山下賢
  • Total Pages: 352
  • Publisher: 中外医学社