Elucidation of mechanism involved in axonal transportation in human peripheral nerve

• Project/Area Number: 18K06936
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Osaka City University
• Principal Investigator: Mingyue Jin 大阪市立大学, 大学院医学研究科, 講師 (60740404)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: alpha-synuclein / Tau / 脳の発生 / 中枢神経系の構築 / 神経幹細胞の分裂と分化 / 軸索輸送 / Unconventional微小管 / α-synuclein / 微小管結合タンパク質 / unconventional微小管 / 神経軸索輸送

Outline of Final Research Achievements

To find out factors involved in unconventional microtubule formation, we performed LC MS/MS analysis and determined α-synuclein (αSyn), Tau, TPPP1, CRMP2 and LC2 (MAP1). Among them, αSyn and Tau are highly expressed microtubule associated proteins in central nervous system, and their abnormal intracellular aggregates in the human brains define multiple neurodegenerative diseases including AD and PD. This indicates that αSyn and tau play important roles in both cognition and movement. In addition, coexistence of αSyn and tau aggregates in tauopathies and synucleinopathies indicates a strong functional cross-talk between two proteins. Despite their disease relevance, the normal physiological functions of αSyn and tau have remained elusive. This is attributable to each single knockout (KO) mouse has not presented overt phenotype or malformations. To address this, we have generated αSyn and tau double knockout (DKO) mouse and found abnormal neurogenesis and gliogenesis in DKO mice.

Academic Significance and Societal Importance of the Research Achievements

これまでαSynとTau生理機能を解析するため、それぞれの単独KOを用いた解析が数多く行われたが、ほとんど表現型を示さなかった。また、神経変性疾患患者の脳病変部の死後解剖では、αSynとtauが一緒に異常蓄積することが多数報告されていることから、機能的な関連性が示唆されている。我々は、生理機能とその関連性を解明するため、αSynとTauを同時に欠損させたDKOマウスを作成し、神経発生とグリア新生に異常を発見した。DKOマウスの解析から中枢神経系の構築におけるαSynとTauの生理機能を解明すれば、神経変性疾患の発症機構の解明や臨床治療法の開発に新しい科学的根拠を提供することになる。

Research Products

• [Journal Article] Enhanced homologous recombination by the modulation of targeting vector ends (2020)
  • Author(s): Hirotsune Shinji、Kiyonari Hiroshi、Jin Mingyue、Kumamoto Kanako、Yoshida Kayo、Shinohara Miki、Watanabe Hitomi、Wynshaw-Boris Anthony、Matsuzaki Fumio
  • Journal Title: Scientific Reports Volume: 10 Pages: 2518-2518
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Functional cross-talk between alpha-synuclein and tau during brain development (2020)
  • Author(s): Mingyue Jin, Shengming Wang and Shinji Hirotsune
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] 微小管結合タンパク質アルファシヌクレインの神経軸索内輸送における機能解析 (2018)
  • Author(s): 鳥羽 栞, 金 明月, 山田 雅巳, 松本 早紀子, 安永 卓生, 福永 優子, 宮澤 淳夫, 小嶋 寛明, 新井 由之, 永井 健治, 広常 真治
  • Organizer: 日本認知症学会