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Cooperative function of alpha-synuclein and tau during brain development

Research Project

Project/Area Number 21K06821
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionOsaka Metropolitan University (2022-2023)
Osaka City University (2021)

Principal Investigator

Jin Mingyue  大阪公立大学, 大学院医学研究科, 研究員 (60740404)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords脳の発生 / 神経発生 / 神経幹細胞の分裂 / 神経細胞の分化 / グリア細胞の発生 / αーシヌクレイン / Tau / 神経細胞の遊走 / アルファシヌクレイン / タウ
Outline of Research at the Start

α-synuclein (αSyn)とtauは脳に高発現する微小管結合たんぱく質で、これらの遺伝子が変異した場合にはパーキンソン病や認知症などの神経変性疾患を発症させる。しかし、この二つのタンパク質の生理機能には未だに不明な点が多い。我々はαSynとtauの機能を解明するため、二つの遺伝子を同時に欠損させたダブルノックアウト(DKO)マウスを作成した。DKOマウスの解析から、αSynとtauの欠損が脳の発生に大きく影響を与えることが分かった。本研究では、in uteroとin vivo解析を組み合わせ、脳発生期の中枢神経系の構築と脳高次機能の維持におけるαSynとtauの生理機能の解明に挑む。

Outline of Final Research Achievements

Abnormal intracellular aggregation of αSyn and/or tau in the human brains define multiple forms of neurodegenerative diseases including AD and PD. In addition, coexistence of αSyn and tau aggregates in tauopathies and synucleinopathies indicates a strong cross-talk between two proteins during pathogenesis. Despite their disease relevance, the normal physiological functions and roles of these two proteins have remained elusive, as mice with knockout of either of these proteins do not present overt phenotypes. To address this issue, we simultaneously removed Snca and Mapt genes and generated αSyn-/-tau-/- mice. Through this research project we revealed that αSyn and tau participate in proper neurogenesis and gliogenesis via controlling of Notch signaling and microtubule reorganization. Functional cross-talk between αSyn and tau during corticogenesis will provide new mechanistic insights for the pathogenesis of neurodegenerative diseases caused by aberrant αSyn and/or tau.

Academic Significance and Societal Importance of the Research Achievements

αSynとtauが脳への異常蓄積は神経変性疾患の発症原因となるが、その生理的な機能は十分解明されていない。臨床では、PDは主に運動障害を示すのに対し、AD患者は主に認知機能の低下を示している。しかし、神経変性疾患患者の死後解剖では、αSynとtauが一緒に病変部に異常蓄積することが多数報告され、αSynとtau両者が認知機能と運動の制御に密接に関わっていることを示唆した。本研究は、これまで独立して研究されていたαSynとtauが機能的クロストークを持つことを初めて明らかにし、異なる神経変性疾患にまたがる共通病態、特にPDとAD間に存在する共通関連性を特定するのに重要な証拠を提示することになる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (6 results)

All 2024 2023 2022 2021

All Journal Article (4 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (2 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system.2024

    • Author(s)
      Jin M., Wang S., Gao X., Zou Z., Hirotsune S. and Sun L.
    • Journal Title

      Neural Regen Res

      Volume: 19(4) Issue: 4 Pages: 855-862

    • DOI

      10.4103/1673-5374.382231

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers.2022

    • Author(s)
      1.Jin M., Matsumoto S., Ayaki T., Yamakado H., Taguchi T., Togawa N., Konno A., Hirai H., Nakajima H., Komai S., Ishida R., Chiba S., Takahashi R., Takao T. and Hirotsune S.
    • Journal Title

      Nature Communications

      Volume: 13(1):6880 Issue: 1 Pages: 6880-6880

    • DOI

      10.1038/s41467-022-34555-4

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional cooperation of α-synuclein and tau is essential for proper corticogenesis.2022

    • Author(s)
      2.Wang S., Fu Y., Miyata T., Matsumoto S., Shinoda T., Itoh K., Harada A., Hirotsune S. and Jin M.
    • Journal Title

      The Journal Neuroscience

      Volume: 42(37) Issue: 37 Pages: 7031-7046

    • DOI

      10.1523/jneurosci.0396-22.2022

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Lis1 mutation prevents basal radial glia-like cell production in the mouse2021

    • Author(s)
      Penisson Maxime、Jin Mingyue、Wang Shengming、Hirotsune Shinji、Francis Fiona、Belvindrah Richard
    • Journal Title

      Human Molecular Genetics

      Volume: 31 Issue: 6 Pages: 942-957

    • DOI

      10.1093/hmg/ddab295

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] New posttranslational modification of α-synuclein by tyrosine hydroxylase leads to the formation of cytotoxic oligomers.2023

    • Author(s)
      Jin M., Matsumoto S., Ayaki T., Yamakado H., Taguchi T., Togawa N., Konno A., Hirai H., Nakajima H., Komai S., Takahashi R., Takao T. & Hirotsune S.
    • Organizer
      The 16th Annual Meeting of Chinese Neuroscience Society & The 2nd CJK International Meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional cooperation of α-synuclein and tau in the central nervus system2023

    • Author(s)
      Mingyue Jin, Shengming Wang, Yu Fu, Sakiko Matsumoto, Takaki Miyata, Tomoyasu Shinoda, Kyoko Itoh, Akihiro Harada, Shinji Hirotsune
    • Organizer
      第七届中国神経科学学会神経退行性疾病分会年会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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