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Molecular pathogenesis of neurological diseases caused by disruption of early Golgi quality control system

Research Project

Project/Area Number 17K08621
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General medical chemistry
Research InstitutionWaseda University

Principal Investigator

Hara Taichi  早稲田大学, 人間科学学術院, 教授 (00392374)

Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Discontinued (Fiscal Year 2020)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsγセクレターゼ / Notchシグナル / 初期ゴルジ / Rer1 / 細胞膜タンパク質 / タンパク質品質管理 / 神経幹細胞 / 大脳形成 / 神経難病 / 大脳発生 / ゴルジ体 / γ-secretase / リソソーム / 膜タンパク質 / 脳神経疾患 / 細胞・組織 / 発生・分化 / 蛋白質
Outline of Final Research Achievements

Rer1 is a retrieval receptor for endoplasmic reticulum (ER) retention of various ER membrane proteins and unassembled or immature components of membrane protein complexes. We show that Rer1 is required for the sufficient cell surface expression and activity of γ-secretase complex, which modulates Notch signaling during mouse cerebral cortex development. When Rer1 was depleted in the mouse cerebral cortex, the number of neural stem cells decreased significantly, and malformation of the cerebral cortex was observed. In Rer1-deficient cells, a subpopulation of γ-secretase complexes and components was transported to and degraded in lysosomes, thereby significantly reducing the amount of γ-secretase complex on the cell surface. These results suggest that Rer1 maintains Notch signaling by maintaining sufficient expression of the γ-secretase complex on the cell surface and regulating neural stem cell maintenance during cerebral cortex development.

Academic Significance and Societal Importance of the Research Achievements

γ-セクレターゼはアルツハイマー病の原因の1つであるβアミロイドの産生に働くことが知られています。また、個体発生や幹細胞維持に機能するNotchシグナルの異常は、神経疾患やガンを含めた様々な疾患を引き起こすことが知られています。このことから、今回の成果は、γ-セクレターゼや幹細胞の関係する疾患の発症機構の解明や治療法開発への応用が期待できます。

Report

(4 results)
  • 2020 Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (9 results)

All 2020 2019 2018 2017 Other

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (3 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Remarks (1 results)

  • [Journal Article] Isorhamnetin, a 3’-methoxylated flavonol, enhances the lysosomal proteolysis in J774.1 murine macrophages in a TFEB-independent manner.2020

    • Author(s)
      Sakai Maiko、Ohnishi Kohta、Masuda Masashi、Ohminami Hirokazu、Yamanaka-Okumura Hisami、Hara Taichi、Taketani Yutaka
    • Journal Title

      Bioscience, Biotechnology, and Biochemistry

      Volume: 84 Issue: 6 Pages: 1221-1231

    • DOI

      10.1080/09168451.2020.1727309

    • NAID

      130008108983

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development2018

    • Author(s)
      Taichi Hara, Ikuko Maejima, Tomoko Akuzawa, Rika Hirai, Hisae Kobayashi, Satoshi Tsukamoto, Mika Tsunoda, Aguri Ono, Shota Yamakoshi, Satoshi Oikawa and Ken Sato
    • Journal Title

      PLoS Genetics

      Volume: 14(9) Issue: 9 Pages: e1007647-e1007647

    • DOI

      10.1371/journal.pgen.1007647

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy2018

    • Author(s)
      Higuchi Yujiro、Ohtake Akira、Matsuura Eiji、Ueda Takehiro、Toda Tatsushi、Yamashita Sumimasa、Yamada Kenichiro、Koide Takashi、Yaguchi Hiroaki、Mitsui Jun、Ishiura Hiroyuki、Yoshimura Jun、Doi Koichiro、Morishita Shinichi、Sato Ken、Nakagawa Masanori、Yamaguchi Masamitsu、Tsuji Shoji、Takashima Hiroshi
    • Journal Title

      Brain

      Volume: 印刷中 Issue: 6 Pages: 1622-1636

    • DOI

      10.1093/brain/awy104

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] SFT-4/Surf4 control ER export of soluble cargo proteins and participate in ER exit site organization.2018

    • Author(s)
      Saegusa K, Sato M, Morooka N, Hara T, Sato K
    • Journal Title

      J Cell Biol.

      Volume: 印刷中 Issue: 6 Pages: 2073-2085

    • DOI

      10.1083/jcb.201708115

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Forced lipophagy reveals that lipid droplets are required for early embryonic development in mouse2018

    • Author(s)
      Tatsumi Takayuki、Takayama Kaori、Ishii Shunsuke、Yamamoto Atsushi、Hara Taichi、Minami Naojiro、Miyasaka Naoyuki、Kubota Toshiro、Matsuura Akira、Itakura Eisuke*、Tsukamoto Satoshi*
    • Journal Title

      Development

      Volume: 145 Issue: 4 Pages: 161893-161893

    • DOI

      10.1242/dev.161893

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Application of autophagy to the health promotion2019

    • Author(s)
      Taichi Hara
    • Organizer
      ICoFF2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] オートファジーの健康評価と未病制御への応用2019

    • Author(s)
      原太一
    • Organizer
      日本細胞性粘菌学会第9回例会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 初期ゴルジ品質管理システムによるγ-セクレターゼ複合体形成制御メカニズムの解明2017

    • Author(s)
      原太一
    • Organizer
      日本細胞生物学会
    • Related Report
      2017 Research-status Report
  • [Remarks] 神経幹細胞の増殖に働く遺伝子を発見 ~細胞内品質管理機構の新たな役割~

    • URL

      https://www.waseda.jp/top/news/61349

    • Related Report
      2018 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2022-12-28  

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