Elucidation of the pathogenic mechanisms of ALS/FTLD by identifying molecules related to repeat-associated non-ATG translation

• Project/Area Number: 15K09331
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University (2016-2018); National Center of Neurology and Psychiatry (2015)
• Principal Investigator: Ueyama Morio 大阪大学, 医学系研究科, 特任助教 (20386593)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / リピート関連非ATG翻訳 / 異常伸長リピート / RNAリピート病 / 異常伸長リピートRNA / ショウジョウバエ

Outline of Final Research Achievements

Among the intractable neurodegenerative diseases, amyotrophic lateral sclerosis(ALS) and frontotemporal lobar degeneration(FTLD), the mutation of C9ORF72 gene is the most common mutation in ALS/FTLD(C9ALS/FTLD). The toxicity of proteins produced by repeat-associated non-ATG(RAN) translation is though to be associated with pathogenesis of C9ALS/FTLD. Decreasing this toxicity by regulating RAN translation leads to one of the novel therapy. We identified suppressive modifier(s) of RAN translation by genetic analysis using Drosophila model for ALS/FTLD related to mutation of C9ORF72 gene.

Academic Significance and Societal Importance of the Research Achievements

根治療法が未だにない筋萎縮性側索硬化症と前頭側頭葉変性症に対して、リピート関連非ATG(RAN)翻訳により産生されるタンパク質の毒性を減少させ、発症を抑制することができる因子を発見した。この抑制因子を利用することで新たな治療法開発が進展すると考えられる。同時にこれまで一般的に考えられてた開始コドンATGに依存する翻訳ではない、RAN翻訳のメカニズムの一端を明らかにする研究でもある。

Research Products

• [Int'l Joint Research] Mayo clinic(米国)
• [Int'l Joint Research] Mayo Clinic(米国)
• [Int'l Joint Research] Mayo Clinic(米国)
• [Journal Article] Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS. (2018)
  • Author(s): Azuma Y, Tokuda T, Kushimura Y, Yamamoto I, Mizuta I, Mizuno T, Nakagawa M, Ueyama M, Nagai Y, Iwasaki Y, Yoshida M, Pan D, Yoshida H, Yamaguchi M.
  • Journal Title: Exp Cell Res. Volume: 371 Issue: 2 Pages: 311-321
  • DOI: 10.1016/j.yexcr.2018.08.001
  • Peer Reviewed / Open Access
• [Journal Article] NPM-hMLF1 fusion protein suppresses defects of a Drosophila FTLD model expressing the human FUS gene. (2018)
  • Author(s): Yamamoto I, Azuma Y, Kushimura Y, Yoshida H, Mizuta I, Mizuno T, Ueyama M, Nagai Y, Tokuda T, Yamaguchi M.
  • Journal Title: Sci. Rep. Volume: 8 Issue: 1 Pages: 11291-11291
  • DOI: 10.1038/s41598-018-29716-9
  • Peer Reviewed / Open Access
• [Journal Article] C9orf72連鎖性筋萎縮性側索硬化症・前頭側頭型認知症における病態メカニズム (2018)
  • Author(s): 上山盛夫, 永井義隆
  • Journal Title: 医学のあゆみ Volume: 267 Pages: 817-822
• [Journal Article] Parkinson’s disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through perturbation of endosomal trafficking. (2018)
  • Author(s): Yoshida S, Hasegawa T, Suzuki M, Sugeno N, Kobayashi J, Ueyama M, Fukuda M, Ido-Fujibayashi A, Sekiguchi K, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y and Aoki M.
  • Journal Title: Hum Mol Genet. Volume: 27 Issue: 5 Pages: 823-836
  • DOI: 10.1093/hmg/ddy003
  • Peer Reviewed / Open Access
• [Journal Article] Overexpressin of ter94, Drosophila VCP, improves motor neuron degeneration induced by knockdown of TBPH, Drosophila TDP-43 (2018)
  • Author(s): Kushimura Yukie、Tokuda Takahiro、Azuma Yumiko、Yamamoto Itaru、Mizuta Ikuko、Mizuno Toshiki、Nakagawa Masanori、Ueyama Morio、Nagai Yoshitaka、Yoshida Hideki、Yamaguchi Masamitsu
  • Journal Title: American Journal of Neurodegenerative Disease Volume: 7 Pages: 11-31
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31 (2017)
  • Author(s): Taro Ishiguro, Nozomu Sato, Morio Ueyama, Nobuhiro Fujikake, Chantal Sellier, Akemi Kanegami, Eiichi Tokuda, Bita Zamiri, Terence Gall-Duncan, Mila Mirceta, Yoshiaki Furukawa, 他８名
  • Journal Title: Neuron Volume: 94 Issue: 1 Pages: 108-124
  • DOI: 10.1016/j.neuron.2017.02.046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies. (2015)
  • Author(s): Saitoh Y, Fujikake N, Okamoto Y, Popiel HA, Hatanaka Y, Ueyama M, Suzuki M, Gaumer S, Murata M, Wada K, Nagai Y.
  • Journal Title: J Biol Chem Volume: 290 Issue: 3 Pages: 1442-53
  • DOI: 10.1074/jbc.m114.590281
  • Peer Reviewed / Open Access
• [Journal Article] 神経変性疾患への新しい視点 –プリオン仮説- D.タウ蛋白による前頭側頭葉変性症 (FTLD-Tau) 3.その他のFTLD (異常蛋白の視点から) (2015)
  • Author(s): 上山盛夫、藤掛伸宏、永井義隆
  • Journal Title: Clinical Neurosci. Volume: 33 Pages: 312-314
• [Presentation] ショウジョウバエモデルによるC9-ALS/FTDの病態解明 (2019)
  • Author(s): 上山盛夫、石黒太郎、Tania F. Gendron、今野卓哉、小山哲秀、望月秀樹、和田圭司、石川欣也、小野寺理、Leonard Petrucelli、永井義隆
  • Organizer: 医学系研究科-産業科学研究所懇話会
• [Presentation] C9orf72関連ALS/FTDモデルショウジョウバエにおけるリピート関連非ATG翻訳の制御 (2018)
  • Author(s): 上山盛夫
  • Organizer: 第7回大阪大学神経難病フォーラム
  • Invited
• [Presentation] ショウジョウバエモデルによるC9-ALS/FTDの病態解明 (2018)
  • Author(s): 上山盛夫、石黒太郎、T. F. Gendron、今野卓哉、小山哲秀、望月秀樹、和田圭司、石川欣也、小野寺理、L. Petrucelli、永井義隆
  • Organizer: 第37回日本認知症学会学術集会
• [Presentation] C9orf72関連ALS/FTDモデルショウジョウバエの樹立とリピート関連非ATG翻訳の制御 (2018)
  • Author(s): 上山盛夫、石黒太郎、今野卓哉、小山哲秀、和田圭司、石川欣也、小野寺理、永井義隆
  • Organizer: 第16回神経科学研究会
  • Invited
• [Presentation] Dissection of the pathogenic roles of expanded repeat RNA and dipeptide repeat proteins in C9-ALS/FTD model fly (2018)
  • Author(s): M. Ueyama, T. Ishiguro, T. F. Gendron, T. Konno, A. Koyama, K. Ishikawa, K. Wada, O. Onodera, L. Petrucelli, Y. Nagai
  • Organizer: 5th RNA Metabolism in Neurological Disease Conference
• [Presentation] Regulation of repeat associated non-ATG translation in C9orf72-linked amyotrophic lateral sclerosis/frontotemporal dementia model flies (2017)
  • Author(s): M. Ueyama, T. Ishiguro, N. Fujikake, T. Konno, A. Koyama, O. Onodera, K. Ishikawa, K. Wada, Y. Nagai
  • Organizer: 第40回日本神経科学大会
• [Presentation] ショウジョウバエを用いた筋萎縮性側索硬化症/前頭側頭型認知症の病態形成メカニズムの解明 (2017)
  • Author(s): 上山盛夫
  • Organizer: 日本遺伝学会第89回大会
  • Invited
• [Presentation] Repeat associated non-ATG translation and its regulation in C9orf72-associated amyotrophic lateral sclerosis/frontotemporal dementia model fly (2017)
  • Author(s): M. Ueyama, T. Ishiguro, T. Konno, A. Koyama, K. Wada, K. Ishikawa, O. Onodera, Y. Nagai
  • Organizer: 第58回日本神経学会学術大会・第23回世界神経学会議
  • Int'l Joint Research
• [Presentation] Repeat associated non-ATG translation in Drosophila C9ALS/FTD model (2017)
  • Author(s): M. Ueyama, T. Ishiguro, T. Konno, A. Koyama, O. Onodera, K. Wada, Y. Nagai
  • Organizer: 新学術・PACTALSジョイントミーティング
  • Int'l Joint Research / Invited
• [Presentation] Toxicity of dipeptide repeat proteins in C9 ALS/FTD model fly (2016)
  • Author(s): M. Ueyama, T. Ishiguro, T. F. Gendron, N. Fujikake, T. Konno, A. Koyama, O. Onodera, K. Ishikawa, K. Wada, L. Petrucelli, Y. Nagai
  • Organizer: 11th Brain Research Conference
  • Place of Presentation: Paradise Point, San Diego (U.S.A.)
  • Year and Date: 2016-11-10
  • Int'l Joint Research
• [Presentation] C9ALS/FTDモデルショウジョウバエにおけるジペプチドリピートタンパク質の毒性 (2016)
  • Author(s): 上山盛夫、石黒太郎、T. F. Gendron、藤掛伸宏、今野卓哉、小山哲秀、小野寺理、和田圭司、L. Petrucelli、永井義隆
  • Organizer: 日本遺伝学会第88回大会
  • Place of Presentation: 日本大学国際関係学部北口校舎(静岡県三島市)
  • Year and Date: 2016-09-07
• [Presentation] Repeat associated non-ATG translation in Drosophila C9ALS/FTD model (2016)
  • Author(s): M. Ueyama, T. Ishiguro, N. Fujikake, T. Konno, A. Koyama, O. Onodera, K. Wada, Y. Nagai
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター・神戸ポートピアホテル(兵庫県神戸市)
  • Year and Date: 2016-05-18
• [Presentation] Repeat associated non-ATG translation in Drosophila C9ALS/FTD model (2016)
  • Author(s): M. Ueyama, T. Ishiguro, N. Fujikake, T. Konno, A. Koyama, O. Onodera, K. Wada, Y. Nagai
  • Organizer: 第57回日本神経学会
  • Place of Presentation: 神戸 神戸コンベンションセンター・神戸ポートピアホテル
  • Year and Date: 2016-05-18
• [Presentation] Establishment of a novel animal model of ALS/FTD expressing GGGGCC repeat RNA in Drosophila (2015)
  • Author(s): M. Ueyama, T. Ishiguro, N. Fujikake, T. Konno, A. Koyama, O. Onodera, K. Ishikawa, K. Wada, Y. Nagai
  • Organizer: 10th Brain Research Conference
  • Place of Presentation: Chicago (IL, U.S.A.) The Westin Chicago River North
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] G4C2リピートRNAを発現する新規ALS/FTDモデルショウジョウバエの樹立 (2015)
  • Author(s): 上山盛夫、石黒太郎、藤掛伸宏、今野卓哉、小山哲秀、小野寺理、石川欽也、和田圭司、永井義隆
  • Organizer: 日本遺伝学会第87回大会
  • Place of Presentation: 仙台 東北大学川内北キャンパス
  • Year and Date: 2015-09-24
  • Invited
• [Presentation] Establishment of a novel animal model of ALS and FTD expressing GGGGCC repeat RNA in Drosophila (2015)
  • Author(s): M. Ueyama, T. Ishiguro, N. Fujikake, T. Konno, A. Koyama, O. Onodera, K. Ishikawa, K. Wada, Y. Nagai
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸 神戸国際会議場・神戸国際展示場
  • Year and Date: 2015-07-28
• [Remarks] 大阪大学医学系研究科神経難病認知症探索治療学寄付講座ホームページ http://www2.
  • URL: http://www2.med.osaka-u.ac.jp/neurother/index.html
• [Remarks] 大阪大学医学系研究科神経難病認知症探索治療学寄付講座ホームページ
  • URL: http://www2.med.osaka-u.ac.jp/neurother/index.html
• [Patent(Industrial Property Rights)] 脊髄小脳変性症３１型抑制剤 (2018)
  • Inventor(s): 中谷和彦、柴田知範、永井義隆、上山盛夫
  • Industrial Property Rights Holder: 中谷和彦、柴田知範、永井義隆、上山盛夫
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] 筋萎縮性側索硬化症又は前頭側頭型認知症の予防又は治療剤 (2017)
  • Inventor(s): 永井義隆、上山盛夫
  • Industrial Property Rights Holder: 永井義隆、上山盛夫
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-096111
  • Filing Date: 2017