Therapeutic approach for ER stress in the pathogenesis of ALS

• Project/Area Number: 24591269
• 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, 生命科学研究部, 准教授 (20457592)
• Co-Investigator(Renkei-kenkyūsha): ERA Takumi 熊本大学, 発生医学研究所, 教授 (00273706)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 筋萎縮性側索硬化症 / iPS細胞 / 遠位型ミオパチー / 小胞体ストレス / 運動ニューロン

Outline of Final Research Achievements

We have established iPS cell lines derived from sporadic and familial ALS (SOD1, FUS, and MATR3 mutations) patients. We induced these iPS cells into motor neurons, and examined the expression of endoplasmic reticulum (ER) stress-related molecules. In this experiment, some of ER stress-related molecules including ER chaperones, transcription factors, and pro-apoptotic factors were upregulated in the mutant FUS-expressing cells. However, a few molecules were affected uniformly in the different types of the FUS mutations. A further examination would be required to confirm the results. We also needs to consider limitations under the experiments using iPS cells, such as variability among iPS clones and developmental condition into motor neurons.

Research Products

• [Journal Article] Clinicopathological features of the first Asian family having vocal cord and pharyngeal weakness with distal myopathy due to a MATR3 mutation. (2015)
  • Author(s): Yamashita S, Mori A, Nishida Y, Kurisaki R, Tawara N, Nishikami T, Misumi Y, Ueyama H, Imamura S, Higuchi Y, Hashiguchi A, Higuchi I, Morishita S, Yoshimura J, Uchino M, Takashima H, Tsuji S, Ando Y.
  • Journal Title: Neuropathol Appl Neurobiol Volume: 41 Issue: 3 Pages: 391-398
  • DOI: 10.1111/nan.12179
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Reply to comments on 'gait disturbance due to foot drop is refractory to treatment in nonsystemic vasculitic neuropathy'. (2015)
  • Author(s): Hirahara T, Yamashita S, Misumi Y, Kawakami K, Hori H, Honda S, Watanabe M, Ikeda T, Yamashita T, Maeda Y, Ando Y.
  • Journal Title: Eur Neurol Volume: 73 Issue: 1-2 Pages: 80-80
  • DOI: 10.1159/000368225
  • Peer Reviewed
• [Journal Article] Osteopontin-integrin α(v)β(3) axis is crucial for 5-fluorouracil resistance in oral squamous cell carcinoma. (2015)
  • Author(s): Nakamura T, Shinriki S, Jono H, Ueda M, Nagata M, Guo J, Hayashi M, Yoshida R, Ota T, Ota K, Kawahara K, Nakagawa Y, Yamashita S, Nakayama H, Hiraki A, Shinohara M, Ando Y.
  • Journal Title: FEBS Lett Volume: 589 Issue: 2 Pages: 231-239
  • DOI: 10.1016/j.febslet.2014.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells. (2015)
  • Author(s): Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, Yamashita S, Zijlstra A, Nakayama H, Hiraki A, Shinohara M, Ando Y.
  • Journal Title: Oncotarget Volume: 6 Pages: 1008-1019
  • Peer Reviewed
• [Journal Article] Gait Disturbance due to Foot Drop Is Refractory to Treatment in Nonsystemic Vasculitic Neuropathy (2014)
  • Author(s): Hirahara T, Yamashita S, Misumi Y, Kawakami K, Hori H, Honda S, Watanabe M, Ikeda T, Yamashita T, Maeda Y, Ando Y
  • Journal Title: Eur Neurol Volume: 71 Issue: 3-4 Pages: 180-186
  • DOI: 10.1159/000355531
  • Peer Reviewed
• [Journal Article] Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma: possible link to acquired resistance to anti-VEGF therapy. (2014)
  • Author(s): Guo J, Shinriki S, Su Y, Nakamura T, Hayashi M, Tsuda Y, Murakami Y, Tasaki M, Hide T, Takezaki T, Kuratsu J, Yamashita S, Ueda M, Li JD, Ando Y, Jono H.
  • Journal Title: Oncotarget Volume: 5 Pages: 6353-6364
  • Peer Reviewed / Open Access
• [Journal Article] Decision making of amyotrophic lateral sclerosis patients on noninvasive ventilation to receive tracheostomy positive pressure ventilation. (2014)
  • Author(s): Kurisaki R, Yamashita S, Sakamoto T, Maruyoshi N, Uekawa K, Uchino M, Ando Y.
  • Journal Title: Clin Neurol Neurosurg Volume: 125 Pages: 28-31
  • DOI: 10.1016/j.clineuro.2014.07.008
  • Peer Reviewed
• [Journal Article] Clinical features of Japanese patients with inclusion body myositis. (2014)
  • Author(s): Hori H, Yamashita S, Tawara N, Hirahara T, Kawakami K, Nishikami T, Maeda Y, Ando Y.
  • Journal Title: J Neurol Sci Volume: 346 Issue: 1-2 Pages: 133-137
  • DOI: 10.1016/j.jns.2014.08.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Concomitant accumulation of α-synuclein and TDP-43 in a patient with corticobasal degeneration. (2014)
  • Author(s): Yamashita S, Sakashita N, Yamashita T, Tawara N, Tasaki M, Kawakami K, Komohara Y, Fujiwara Y, Kamikawa M, Nakagawa T, Hirano T, Maeda Y, Hasegawa M, Takeya M, Ando Y
  • Journal Title: Journal of Neurology Volume: 261 Issue: 11 Pages: 2209-2217
  • DOI: 10.1007/s00415-014-7491-8
  • Peer Reviewed / Open Access
• [Journal Article] Drastic therapy for listerial brain abscess involving combined hyperbaric oxygen therapy and antimicrobial agents. (2014)
  • Author(s): Nakahara K, Yamashita S, Ideo K, Shindo S, Suga T, Ueda A, Honda S, Hirahara T, Watanabe M, Yamashita T, Maeda Y, Yonemochi Y, Takita T, Ando Y.
  • Journal Title: J Clin Neurol Volume: 10 Issue: 4 Pages: 358-62
  • DOI: 10.3988/jcn.2014.10.4.358
  • Peer Reviewed / Open Access
• [Journal Article] New type of Sendai virus vector provides transgene-free iPS cells derived from chimpanzee blood. (2014)
  • Author(s): Fujie Y, Fusaki N, Katayama T, Hamasaki M, Soejima Y, Soga M, Ban H, Hasegawa M, Yamashita S, Kimura S, Suzuki S, Matsuzawa T, Akari H, Era T
  • Journal Title: PloS one Volume: 9 Issue: 12 Pages: 113052-113052
  • DOI: 10.1371/journal.pone.0113052
  • Peer Reviewed / Open Access
• [Journal Article] Stromal Expression of Neutrophil Gelatinase-Associated Lipocalin Correlates with Poor Differentiation and Adverse Prognosis in Oral Squamous Cell Carcinoma. (2014)
  • Author(s): Shinriki S., Jono H., Ueda M., Obayashi K., Nakamura T., Ota K., Ota T., Sueyoshi T., Guo J., Hayashi M., Hiraki A., Nakayama H., Yamashita S., Shinohara M., & Ando Y.
  • Journal Title: Histopathology Volume: 64 Issue: 3 Pages: 353-364
  • DOI: 10.1111/his.12293
  • Peer Reviewed
• [Journal Article] Clinical significance of CYLD downregulation in breast cancer. (2014)
  • Author(s): Hayashi M, Jono H, Shinriki S, Nakamura T, Guo J, Sueta A, Tomiguchi M, Fujiwara S, Yamamoto-Ibusuki M, Murakami K, Yamashita S, Yamamoto Y, Li JD, Iwase H, Ando Y.
  • Journal Title: Breast Cancer Res Treat. Volume: 143 Issue: 3 Pages: 447-457
  • DOI: 10.1007/s10549-013-2824-3
  • Peer Reviewed
• [Journal Article] Multiple system atrophy in a patient with primary ciliary dyskinesia. (2013)
  • Author(s): Sakaguchi H., Yamashita S., Suga T., Kimura E., Maeda Y., Hirano T., & Uchino M.
  • Journal Title: Neurol Asia Volume: 18 Pages: 101-103
  • Peer Reviewed
• [Journal Article] Bilateral basal ganglia lesions as initial manifestation of CNS invasion in adult T-cell leukemia (2013)
  • Author(s): Matsuo Y, Yamashita S, Honda S, Nakajima M, Ueda A, Hirahara T, Yamashita T, Maeda Y, Hirano T, Ando Y
  • Journal Title: J Neurol Sci Volume: 327(1-2) Issue: 1-2 Pages: 63-4
  • DOI: 10.1016/j.jns.2013.01.035
  • Peer Reviewed
• [Journal Article] Muscle biopsy findings predictive of malignancy in rare infiltrative dermatomyositis (2013)
  • Author(s): Uchino M, Yamashita S, Uchino K, Mori A, Hara A, Suga T, Hirahara T, Koide T, Kimura E, Yamashita T, Ueda A, Kurisaki R, Suzuki J, Honda S, Maeda Y, Hirano T, Ando Y
  • Journal Title: Clin Neurol Neurosurg Volume: 115(5) Issue: 5 Pages: 603-6
  • DOI: 10.1016/j.clineuro.2012.07.019
  • Peer Reviewed
• [Journal Article] Optineurin is potentially associated with TDP-43 and involved in the pathogenesis of inclusion body myositis. (2013)
  • Author(s): Yamashita S., Kimura E., Tawara N., Sakaguchi H., Nakama T., Maeda Y., Hirano T., Uchino M., & Ando Y.
  • Journal Title: Neuropathol. Appl. Neurobiol. Volume: 39 Issue: 4 Pages: 406-416
  • DOI: 10.1111/j.1365-2990.2012.01297.x
  • Peer Reviewed
• [Journal Article] Efficient and reproducible myogenic differentiation from human iPS cells: prospects for modeling Miyoshi Myopathy in vitro. (2013)
  • Author(s): Tanaka, A., et al
  • Journal Title: PLoS ONE Volume: 8(4) Issue: 4 Pages: e61540-e61540
  • DOI: 10.1371/journal.pone.0061540
  • Peer Reviewed
• [Journal Article] Heatstroke in patients with Parkinson's disease (2012)
  • Author(s): Satoshi Yamashita
  • Journal Title: Neurological Sciences Volume: 33 Issue: 3 Pages: 685-687
  • DOI: 10.1007/s10072-011-0842-7
  • Peer Reviewed
• [Journal Article] Significant CMAP decrement by repetitive nerve stimulation is more frequent in median than ulnar nerves of patients with amyotrophic lateral sclerosis (2012)
  • Author(s): Satoshi Yamashita, Hideya Sakaguchi, Akira Mori
  • Journal Title: Muscle Nerve Volume: 45 Issue: 3 Pages: 426-428
  • DOI: 10.1002/mus.22301
  • NAID: 120005123115
  • Peer Reviewed
• [Journal Article] Long-term outcome of polymyositis treated with high single-dose alternate-day prednisolone therapy (2012)
  • Author(s): Makoto Uchino
  • Journal Title: European Neurology Volume: 68 Issue: 2 Pages: 117-121
  • DOI: 10.1159/000338474
  • Peer Reviewed
• [Journal Article] Myasthenic crisis patients who require intensive care unit management (2012)
  • Author(s): Hideya Sakaguchi
  • Journal Title: Muscle and Nerve Volume: 46 Issue: 3 Pages: 440-442
  • DOI: 10.1002/mus.23445
  • Peer Reviewed
• [Journal Article] Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS : possible association of mental retardation with this mutation (2011)
  • Author(s): Satoshi Yamashita, Akira Mori, Hideya Sakaguchi
  • Journal Title: Journal of Neurplogy Volume: 259 Issue: 6 Pages: 1039-1044
  • DOI: 10.1007/s00415-011-6292-6
  • Peer Reviewed
• [Presentation] Analyses of the pathogenesis in muscle-specific wild-type TDP-43 transgenic mice. (2014)
  • Author(s): Satoshi Yamashita, Kensuke Kawakami, Tomo Nishikami, Nozomu Tawara, Yasushi Maeda, Yukio Ando.
  • Organizer: 19th International Congress of the World Muscle Society
  • Place of Presentation: Langenbeck-Virchow-Haus, Berlin, Germany
  • Year and Date: 2014-10-08
• [Presentation] Cytoplasmic 5’-nucleotidase 1A are aggregated in type 2 fiber in sporadic inclusion body myositis. (2014)
  • Author(s): Nozomu Tawara, Satoshi Yamashita, Tomo Nishikami, Kensuke Kawakami, Akie Tawara, Hiroko Hori, Tomoo Hirahara, Yasushi Maeda, Yukio Ando.
  • Organizer: 19th International Congress of the World Muscle Society
  • Place of Presentation: Langenbeck-Virchow-Haus, Berlin, Germany
  • Year and Date: 2014-10-08
• [Presentation] The first Asian family having vocal cord and pharyngeal weakness with distal myopathy due to a MATR3 mutation. (2014)
  • Author(s): Tomo Nishikami, Satoshi Yamashita, Nozomu Tawara, Akira Mori, Hiroko Hori, Tomoo Hirahara, Yasushi Maeda, Yukio Ando.
  • Organizer: 19th International Congress of the World Muscle Society
  • Place of Presentation: Langenbeck-Virchow-Haus, Berlin, Germany
  • Year and Date: 2014-10-08
• [Presentation] 診断から18年間経過観察しえた大脳皮質基底核変性症の剖検例-αシヌクレインとTDP-43、タウ蛋白の局在について-. (2014)
  • Author(s): 山下 賢、坂下直実、山下太郎、植田明彦、田崎雅義、川上賢祐、菰原義弘、藤原章雄、上川将史、中川雄伸、前田 寧、長谷川成人、竹屋元裕、安東由喜雄.
  • Organizer: 第55回日本神経病理学会総会
  • Place of Presentation: 学術総合センター、東京、日本
  • Year and Date: 2014-06-06
• [Presentation] アジア初の声帯および咽頭麻痺を伴う遠位型ミオパチー（MPD2/ VCPDM）の1家系2症例に関する多角的検討. (2014)
  • Author(s): 西上 朋、山下 賢、俵 望、森 麗、西田泰斗、内野克尚、永利聡仁、栗﨑玲一、中西俊人、堀 寛子、平原智雄、渡邉聖樹、上山秀嗣、山下太郎、前田寧、安東由喜雄.
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡、日本
  • Year and Date: 2014-05-24
• [Presentation] 孤発性封入体筋炎の自己抗原NT5C1Aはタイプ２線維に凝集している. (2014)
  • Author(s): 俵 望, 山下 賢, 西上 朋, 川上 賢祐, 前田 寧, 安東 由喜雄.
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡、日本
  • Year and Date: 2014-05-23
• [Presentation] 封入体筋炎におけるCylindromatosis蛋白発現の検討. (2014)
  • Author(s): 山元雅典、俵 望、山下 賢、児玉美里、中村ひとみ、西上 朋、川上賢祐、安東由喜雄.
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡、日本
  • Year and Date: 2014-05-23
• [Presentation] 筋特異的なTDP-43発現によるIBMモデルマウス作製と病態解析. (2014)
  • Author(s): 山下 賢，川上賢祐, 西上 朋, 俵 望, 安東由喜雄.
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡、日本
  • Year and Date: 2014-05-22
• [Presentation] DCTN1遺伝子多型を有し、異なる神経症候を呈した1家系母子例. (2014)
  • Author(s): 髙松孝太郎，山下賢，岩田有生，進藤誠悟，三隅洋平，山下太郎，安東由喜雄.
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡、日本
  • Year and Date: 2014-05-22
• [Presentation] 筋萎縮性側索硬化症（ALS）診断における反復刺激試験の有用性の検討. (2014)
  • Author(s): 森 麗、山下 賢、堀 寛子、俵 明恵、中原 圭一、高松 孝太郎、三隅 洋平、安東 由喜雄.
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡、日本
  • Year and Date: 2014-05-21
• [Presentation] Involvement of optineurin as well as TDP-43 in the pathogenesis of inclusion body myositis (2013)
  • Author(s): Satoshi Yamashita
  • Organizer: 18th International WMS Congress
  • Place of Presentation: Asilomar Conference Grounds, Asilomar, California, USA
• [Presentation] ＦＵＳ／ＴＬＳ変異を有する弧発性若年性ＡＬＳの２例：変異蛋白の細胞内局在の検討 (2012)
  • Author(s): 山下 賢
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京都）
• [Presentation] Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: Possible association of mental retardation with this mutation (2012)
  • Author(s): Satoshi Yamashita
  • Organizer: 23th international Symposium on ALS/MND
  • Place of Presentation: Sheraton Hotel and Towers, Chicago, IL, USA
• [Presentation] Significant CMAP decrement by repetitive nerve stimulation is more frequent in median than ulnar nerves of patients with amyotrophic lateral sclerosis (2012)
  • Author(s): Akira Mori
  • Organizer: 23th international Symposium on ALS/MND
  • Place of Presentation: Sheraton Hotel and Towers, Chicago, IL, USA
• [Presentation] Involvement of optineurin as well as TDP-43 and involved in the pathogenesis of inclusion body myositis.
  • Author(s): Yamashita S, Tawara N, Kawakami K, Nishikami T, Maeda Y, Ando Y.
  • Organizer: 18th International Congress of the World Muscle Society
  • Place of Presentation: Asilomar Conference Grounds, California, USA
• [Presentation] 封入体筋炎の病態におけるTDP-43とoptineurinの重要性.
  • Author(s): 山下 賢, 川上賢祐, 俵 望, 堀 寛子, 木村 円, 前田 寧, 安東由喜雄.
  • Organizer: 第54回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム、東京
• [Book] 神経内科研修ノート 肝性脳症 (2015)
  • Author(s): 山下賢, 安東由喜雄
  • Publisher: 診断と治療社
• [Book] 代謝性ミオパチー 薬剤による筋障害（薬剤性ミオパチー） (2014)
  • Author(s): 山下賢
  • Publisher: 診断と治療社
• [Book] 筋疾患診療ハンドブック (2013)
  • Author(s): 山下賢，森麗．
  • Total Pages: 206
  • Publisher: 中外医学社