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Cellular cholesterol homeostasis and luminal pH of the Golgi apparatus

Research Project

Project/Area Number 19K07276
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48010:Anatomy-related
Research InstitutionJuntendo University

Principal Investigator

Sou Yu-shin  順天堂大学, 医学部, 助教 (60576221)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsゴルジ体 / GPHR / SREBP2 / コレステロール / 神経細胞 / N2A / オルガネラ酸性環境 / プルキンエ細胞 / バスケット細胞 / SREBP
Outline of Research at the Start

酸性オルガネラであるゴルジ体、エンドソームやリソソームなどの内腔は酸性pHに保持されている。この酸性環境は細胞の生存に必須であり、その破綻が種々の疾患の発症要因であることが報告されている。酸性オルガネラの1つ、ゴルジ体の形態異常は種々のヒト疾患病巣部の細胞において観察される。しかしながら、内腔の酸性環境の破綻と病態発症の因果関係には不明な点が多く残っている。そこで、本研究課題では、ゴルジ体局在イオンチャネルGPHRに着目し、ゴルジ体の酸性環境破綻に起因する形態異常や細胞内変動の解明を目指す。

Outline of Final Research Achievements

Organelles located in the secretory pathway are collectively called acidic organelles, and their lumen is maintained in an acidic condition. To gain insight into the luminal acidic pH of the Golgi apparatus in neuronal cells, we analyzed GPHR knockout mice which can be manipulating the Golgi specific acidic condition. We confirmed that loss of GPHR affects cholesterol biosynthesis via SREBP2 activation in neuronal cells. Morphological analysis provided evidence that GPHR-deficiency course the inhibition neurite outgrowth. These results suggesting that the acidic pH of the Golgi apparatus contributes to cholesterol biosynthesis via activation of SREBP2 in the neuronal cells, and that inhibition lead to suppresses neuronal morphogenesis.

Academic Significance and Societal Importance of the Research Achievements

酸性オルガネラの解析において、ゴルジ体の酸性環境維持機構の生理機能やその破綻による病態生理は、そのほとんどが培養細胞を用いた解析に留まっていた。そこで、本研究課題では、ゴルジ体酸性環境維持に必須な遺伝子GPHRの遺伝子改変動物を用いて、組織レベルにおけるゴルジ体酸性環境維持機構の生理的意義とその破綻に伴うゴルジ体形態異常の病態生理的意義を明らかにした。今後はより詳細な病態発症の分子機構を明らかにすることで、ゴルジ体酸性環境の破綻に起因する病態発症機序の解明および新たな治療法の発見に繋がると期待できる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (8 results)

All 2022 2021 2019 Other

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

  • [Journal Article] Phase-separated protein droplets of amyotrophic lateral sclerosis-associated p62/SQSTM1 mutants show reduced inner fluidity2021

    • Author(s)
      Faruk MO, Ichimura Y, Kageyama S, Komatsu-Hirota S, El-Gowily AH, Sou YS, Koike M, Noda NN, Komatsu M.
    • Journal Title

      J Biol Chem

      Volume: 297 Issue: 6 Pages: 101405-101405

    • DOI

      10.1016/j.jbc.2021.101405

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response2021

    • Author(s)
      Kageyama S, Gudmundsson SR, Sou YS, Ichimura Y, Tamura N, Kazuno S, Ueno T, Miura Y, Noshiro D, Abe M, Mizushima T, Miura N, Okuda S, Motohashi H, Lee JA, Sakimura K, Ohe T, Noda NN, Waguri S, Eskelinen EL, Komatsu M.
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 16-16

    • DOI

      10.1038/s41467-020-20185-1

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cerebellar Neurodegeneration and Neuronal Circuit Remodeling in Golgi pH Regulator-Deficient Mice2019

    • Author(s)
      Sou Yu-shin、Kakuta Soichiro、Kamikubo Yuji、Niisato Kazue、Sakurai Takashi、Parajuli Laxmi Kumar、Tanida Isei、Saito Hiromitsu、Suzuki Noboru、Sakimura Kenji、Maeda Yusuke、Kinoshita Taroh、Uchiyama Yasuo、Koike Masato
    • Journal Title

      eNeuro

      Volume: 6 Issue: 3 Pages: 0427-18

    • DOI

      10.1523/eneuro.0427-18.2019

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of autophagy impairs physiological steatosis by accumulation of NCoR1.2019

    • Author(s)
      Takahashi SS, Sou YS, Saito T, Kuma A, Yabe T, Sugiura Y, Lee HC, Suematsu M, Yokomizo T, Koike M, Terai S, Mizushima N, Waguri S, Komatsu M.
    • Journal Title

      Life Sci Alliance.

      Volume: 3 Issue: 1 Pages: 201900513-201900513

    • DOI

      10.26508/lsa.201900513

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] ゴルジ体酸性環境が担う適切な糖鎖修飾の変化がリソソームに与える影響2022

    • Author(s)
      曽友深、前田祐輔、木下タロウ、小池正人
    • Organizer
      第127回日本解剖学会総会・全国学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ゴルジ体酸性環境による糖鎖修飾の制御メカニズム2021

    • Author(s)
      曽 友深
    • Organizer
      第126回日本解剖学会総会・全国学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 小脳神経系におけるゴルジ体酸性環境の重要性2019

    • Author(s)
      曽 友深
    • Organizer
      NEURO2019
    • Related Report
      2019 Research-status Report
  • [Remarks] 順天堂大学大学院 医学研究科 神経機能構造学講座 医学部 神経生物学・形態学講座

    • URL

      https://juntendo-cellbio.jp/

    • Related Report
      2021 Annual Research Report 2020 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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