Elucidation of pathogenesis and development of treatment for spinocerebellar ataxia due to a non-coding microsatellite repeat expansion

• Project/Area Number: 16K09665
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Gunma University
• Principal Investigator: Ikeda Yoshio 群馬大学, 大学院医学系研究科, 教授 (00282400)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脊髄小脳変性症 / 脊髄小脳失調症 / マイクロサテライトリピート / リピート伸長変異 / siRNA / SCA36 / マイクロサテライト・リピート / RNA foci / RAN translation / SCA8 / 病態修飾治療

Outline of Final Research Achievements

We developed a cell culture model for spinocerebellar ataxia type 36 (SCA36), which is caused by a GGCCTG repeat expansion mutation located in the untranslated region of the causative gene. This model reproduced the RNA foci or the repeat-associated non-ATG translation (RANT)-associated proteins, which are associated to cell death. When siRNAs against the transcriptional elongation factor yeast Spt4/Spt5 orthologues were introduced to the SCA36 cell culture model, it was revealed that the cytotoxicity is reduced through the suppression of expression of (GGCCUG)exp transcripts through Spt4/Spt5 silencing.

Academic Significance and Societal Importance of the Research Achievements

脊髄小脳失調症36型(SCA36)の病態を再現する培養細胞モデルを確立し、これを用いてSpt4/Spt5に対するsiRNAによる細胞毒性減少効果を明らかにした。本研究による成果はSCA36に対する治療法を今後開発する上での重要な基礎データになると考えられた。

Research Products

• [Journal Article] Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity (2019)
  • Author(s): Furuta Natsumi、Tsukagoshi Setsuki、Hirayanagi Kimitoshi、Ikeda Yoshio
  • Journal Title: Brain Research Volume: 1711 Pages: 29-40
  • DOI: 10.1016/j.brainres.2018.12.045
  • Peer Reviewed
• [Journal Article] Putaminal iron deposition precedes MSA-P onset by 2 years (2018)
  • Author(s): Kikuchi Yutaro、Shibata Makoto、Hirayanagi Kimitoshi、Nagashima Kazuaki、Mihara Ban、Ikeda Yoshio
  • Journal Title: Neurology Volume: 90 Issue: 23 Pages: 1071-1072
  • DOI: 10.1212/wnl.0000000000005637
  • Peer Reviewed
• [Journal Article] Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome (2018)
  • Author(s): Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Kimura M, Hama Y, Matsushima M, Fujioka S, Kano T, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Ohtsuka T, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 819-819
  • DOI: 10.1038/s41598-018-19198-0
  • NAID: 120006377499
  • Peer Reviewed / Open Access
• [Journal Article] Response to the letter to the editor regarding an article “Bilateral striatal necrosis caused by a founder mitochondrial 14459G>A mutation in two independent Japanese families” (2017)
  • Author(s): Hirayanagi Kimitoshi、Ikeda Yoshio
  • Journal Title: J Neurol Sci Volume: 380 Pages: 283-284
  • DOI: 10.1016/j.jns.2017.07.005
  • Peer Reviewed
• [Journal Article] Bilateral striatal necrosis caused by a founder mitochondrial 14459G > A mutation in two independent Japanese families (2017)
  • Author(s): Hirayanagi Kimitoshi、Okamoto Yuji、Takai Eriko、Ishizawa Kunihiko、Makioka Kouki、Fujita Yukio、Kaneko Yuka、Tanaka Makoto、Takashima Hiroshi、Ikeda Yoshio
  • Journal Title: J Neurol Sci Volume: 378 Pages: 177-181
  • DOI: 10.1016/j.jns.2017.05.015
  • Peer Reviewed
• [Journal Article] A novel GBE1 mutation in a Japanese family with adult polyglucosan body disease. (2017)
  • Author(s): Yasuo Harigaya, Takashi Matsukawa, Yukio Fujita, Kazuyuki Mizushima,Hiroyuki Ishiura, Jun Mitsui, Shinichi Morishita, Mikio Shoji, Yoshio Ikeda, and Shoji Tsuji.
  • Journal Title: Neurol Genet Volume: 3 Issue: 2
  • DOI: 10.1212/nxg.0000000000000138
  • Peer Reviewed / Open Access
• [Journal Article] Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts. (2017)
  • Author(s): Iwama K, Mizuguchi T, Takanashi JI, Shibayama H, Shichiji M, Ito S, Oguni H, Yamamoto T, Sekine A, Nagamine S, Ikeda Y, Nishida H, Kumada S, Yoshida T, Awaya T, Tanaka R, Chikuchi R, Niwa H, Oka YI, Miyatake S, Nakashima M, Takata A, Miyake N, Ito S, Saitsu H, Matsumoto N.
  • Journal Title: Clinical Genetics Volume: - Issue: 2 Pages: 180-187
  • DOI: 10.1111/cge.12991
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] An analysis of prognostic factors after percutaneous endoscopic gastronomy palcement in Japansese patients with amyotrophic lateral sclerosis (2017)
  • Author(s): Nagashima K, Furuta N, Makioka K, Fujita Y, Ikeda M, Ikeda Y
  • Journal Title: J Neurol Sci Volume: 376 Pages: 202-205
  • DOI: 10.1016/j.jns.2017.03.029
  • Peer Reviewed
• [Book] 脊髄小脳変性症・多系統萎縮症診療ガイドライン2018 (2018)
  • Author(s): 日本神経学会、「脊髄小脳変性症・多系統萎縮症診療ガイドライン」作成委員会
  • Total Pages: 280
  • Publisher: 南江堂
  • ISBN: 9784524246175
• [Book] 人体の細胞生物学 : カラー図解 (2018)
  • Author(s): 坂井 建雄、石崎 泰樹
  • Total Pages: 271
  • Publisher: 日本医事新報社
  • ISBN: 9784784932320
• [Book] Annual Review 神経 2018：遺伝性脊髄小脳変性症分子病態の最新トピックス. (2018)
  • Author(s): 池田佳生
  • Total Pages: 10
  • Publisher: 中外医学社
• [Remarks] 研究紹介：脊髄小脳変性症の分子病態解明と治療開発研究
  • URL: http://neurology.dept.med.gunma-u.ac.jp/class/kenkyu%20shokai%20yoshio%20ikeda.html