Analysis of microRNA in oligodendrocyte degeneration

• Project/Area Number: 17K07099
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Sapporo Medical University
• Principal Investigator: Hisahara Shin 札幌医科大学, 医学部, 准教授 (80336403)
• Co-Investigator(Kenkyū-buntansha): 堀尾 嘉幸 札幌医科大学, 医学部, 教授 (30181530) ; 下濱 俊 札幌医科大学, 医学部, 教授 (60235687)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: オリゴデンドロサイト / 変性 / マイクロRNA / 初代培養 / 多発性硬化症 / SIRTファミリー / 分化 / 前駆細胞

Outline of Final Research Achievements

We successfully established collect oligodendrocyte premature cells (OPC) in the primary culture from mouse embryonic brain, however, it was difficult to identify significant miRNA derived from differentiating OPCs. So we modified our strategy, showing the function of SIRTs in the OPC differentiation. Knockdown of not only SIRT1 but also SIRT2 promoted increasing number of well-differentiated OLGs. The mature OLGs show broadly cellular distribution of OLG-specific cytoskeleton-related molecules, βIV-tubulin and tubulin polymerization promoting protein (TPPP). Although βIV-tubulin and TPPP are not directly associated with SIRT1/SIRT2, we demonstrated that knockdown of SIRT1 and SIRT2 independently give rise to induction of these molecules. Our findings indicate that SIRT1 and SIRT2 inhibitory regulate OLG differentiation, at least from OLG progenitor cells, through the suppression of expression of OLG-specific cytoskeleton-related molecules and their subcellular distribution.

Academic Significance and Societal Importance of the Research Achievements

MSは本邦でも罹患率が上昇の一途をたどる神経難病の一つである。これまでのMS研究は免疫細胞による炎症性中枢神経障害の機序を解明するものがほとんどであり、現在のところ副腎皮質ホルモンや疾患調整薬などで炎症反応を抑制し臨床的再発を減少させても脳萎縮や認知機能を含めた長期的な機能予後の悪化を制御することは困難であることが次第に明らかにされている。本研究はMSの発症機序において免疫異常・炎症とは独立したOLGの一次的変性過程によって障害される何らかの分子メカニズムが存在すると仮定し、そのメカニズムにmiRNAが関与していると考えることが発端になっており、以下の特色と意義があると考えられる。

Research Products

• [Journal Article] Severe Mononeuritis Multiplex due to Rheumatoid Vasculitis in Rheumatoid Arthritis in Sustained Clinical Remission for Decades (2020)
  • Author(s): Tanemoto Masanobu、Hisahara Shin、Hirose Bungo、Ikeda Kazuna、Matsushita Takashi、Suzuki Shuichiro、Manabe Tatsuo、Imai Tomihiro、Shimohama Shun
  • Journal Title: Internal Medicine Volume: 59 Issue: 5 Pages: 705-710
  • DOI: 10.2169/internalmedicine.3866-19
  • NAID: 130007804520
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-03-01
  • Peer Reviewed
• [Journal Article] Evaluation of Mitochondrial Oxidative Stress in the Brain of a Transgenic Mouse Model of Alzheimer's Disease by in vitro Electron Paramagnetic Resonance Spectroscopy. (2019)
  • Author(s): Manabe T, Matsumura A, Yokokawa K, Saito T, Fujikura M, Iwahara N, Matsushita T, Suzuki S, Hisahara S, Kawamata J, Suzuki H, Emoto MC, Fujii HG, Shimohama S.
  • Journal Title: Journal of Alzheimer's disease Volume: 67 Issue: 3 Pages: 1079-1087
  • DOI: 10.3233/jad-180985
  • Peer Reviewed
• [Journal Article] CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway. (2019)
  • Author(s): Fujikura M, Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Manabe T, Matsushita T, Suzuki S, Shimohama S.
  • Journal Title: J Alzheimers Dis. Volume: 68 Issue: 1 Pages: 323-337
  • DOI: 10.3233/jad-180904
  • Peer Reviewed
• [Journal Article] Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress (2019)
  • Author(s): Yokokawa Kazuki、Iwahara Naotoshi、Hisahara Shin、Emoto Miho C.、Saito Taro、Suzuki Hiromi、Manabe Tatsuo、Matsumura Akihiro、Matsushita Takashi、Suzuki Syuuichirou、Kawamata Jun、Sato-Akaba Hideo、Fujii Hirotada G.、Shimohama Shun
  • Journal Title: Journal of Alzheimer's Disease Volume: 72 Issue: 3 Pages: 867-884
  • DOI: 10.3233/jad-190817
  • Peer Reviewed / Open Access
• [Journal Article] Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease (2019)
  • Author(s): Saito Taro、Hisahara Shin、Iwahara Naotoshi、Emoto Miho C.、Yokokawa Kazuki、Suzuki Hiromi、Manabe Tatsuo、Matsumura Akihiro、Suzuki Syuuichirou、Matsushita Takashi、Kawamata Jun、Sato-Akaba Hideo、Fujii Hirotada G.、Shimohama Shun
  • Journal Title: Free Radical Biology and Medicine Volume: 145 Pages: 20-32
  • DOI: 10.1016/j.freeradbiomed.2019.09.014
  • Peer Reviewed
• [Journal Article] Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis (2018)
  • Author(s): Miyazaki Yusei、Niino Masaaki、Takahashi Eri、Suzuki Masako、Mizuno Masanori、Hisahara Shin、Fukazawa Toshiyuki、Amino Itaru、Nakano Fumihito、Nakamura Masakazu、Akimoto Sachiko、Minami Naoya、Fujiki Naoto、Doi Shizuki、Shimohama Shun、Terayama Yasuo、Kikuchi Seiji
  • Journal Title: Clinical Immunology Volume: 187 Pages: 95-101
  • DOI: 10.1016/j.clim.2017.10.009
  • Peer Reviewed
• [Presentation] Deacetylase SIRT1 and SIRT2 regulate cytoskeleton-related molecules in oligodendrocyte cell lines (2019)
  • Author(s): Shin Hisahara， Naotoshi Iwahara， Tatsuo Manabe， Mai Fujikura， Taro Saito， Kazuki Yokokawa， Takashi Matsushita， Akihiro Matsumura， Syuuichirou Suzuki， Jun Kawamata， Shun Shimohama
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] 神経変性疾患に対する脳血流123I-IMP-SPECTにおけるCIScore解析の検証 (2019)
  • Author(s): 松村 晃寛, 浅沼 治, 横川 和樹, 齋藤 太郎, 藤倉 舞, 岩原 直敏, 眞部 建郎, 津田 玲子, 山本 大輔, 松下 隆司, 鈴木 秀一郎, 臼井 桂子, 齊藤 正樹, 久原 真, 川又 純, 今井 富裕, 下濱 俊
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Effectiveness of galantamine treatment in normal cognition phase of APPswe/PS1dE9 mice (2019)
  • Author(s): 齋藤 太郎, 横川 和樹, 藤倉 舞, 眞部 建郎, 岩原 直敏, 久原 真, 松村 晃寛, 鈴木 秀一郎, 松下 隆司, 川又 純, 鈴木 紘美, 江本 美穂, 藤井 博匡, 下濱 俊
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Rat Bone Marrow-derived MSCs Attenuate Oxidative Stress and Neuroinflammation in APP/PS1 mice (2019)
  • Author(s): 横川 和樹, 岩原 直敏, 江本 美穂, 久原 真, 齋藤 太郎, 藤倉 舞, 真部 建郎, 松下 隆司, 松村 晃寛, 鈴木 秀一郎, 川又 純, 藤井 博匡, 下濱 俊
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Time course of intranigral invasion of immunocytes in 6-OHDA-induced Parkinson's disease rat model (2019)
  • Author(s): 鈴木 秀一郎, 鈴木 紘美, 齋藤 太郎, 横川 和樹, 藤倉 舞, 真部 健郎, 岩原 直敏, 松下 隆司, 松村 晃寛, 久原 真, 川又 純, 下濱 俊
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Involvement of SIRTs in the morphological change of human oligodendrocyte cell lines (2018)
  • Author(s): Shin Hisahara， Naotoshi Iwahara， Tatsuo Manabe， Mai Fujikura， Taro Saito， Kazukia Yokokawa， Naoki Gamo， Takashi Matsushita， Matsumura Akihiro， Syuuichirou Suzuki， Jun Kawamata， Shun Shimohama
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Deacetylase SIRTs regulate differentiation of oligodendrocyte and modulate distribution of oligodendrocyte-specific cytoskeleton-related molecules (2017)
  • Author(s): Shin Hisahara, Naotoshi Iwahara, Tatsuo Manabe, Mai Fujikura, Taro Saito, Kazuki Yokokawa, Akihiro Matsumura, Syuuichirou Suzuki, Jun Kawamata, Shun Shimohama
  • Organizer: 23rd Annual Meeting of World Congress of Neurology
  • Int'l Joint Research