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2020 Fiscal Year Annual Research Report

核酸を分解する膜透過型オートファジーのメカニズムと疾患との関連

Research Project

Project/Area Number 18F18384
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

株田 智弘  国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第四部, 室長 (70535765)

Co-Investigator(Kenkyū-buntansha) CONTU VIORICA  国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第四部, 外国人特別研究員
Project Period (FY) 2018-11-09 – 2021-03-31
Keywordsautophagy
Outline of Annual Research Achievements

Because already known lysosomal degradation pathways cannot fully account for total levels of lysosomal proteolysis in cells (Tong et al. 2020) and protein accumulation in cells is a hallmark of neurodegenerative diseases, we sought for novel protein degradation pathways in lysosomes.
We found that cytosolic proteins are imported into lysosomes by a direct uptake mechanism which is distinct from any known pathways, and then degraded. SIDT2 mediates the translocation and contributes conspicuously to the lysosomal degradation of a wide range of cytosolic proteins in cells at the constitutive level (nutrient-rich condition). We also identified a dominant-negative mutation in SIDT2 which causes familial neuropathy and distal myopathy with rimmed vacuoles in humans and confirmed that Sidt2 knockout mice recapitulate the typical features of the disease.
These results reveal previously unknown pathway of proteolysis in lysosomes and highlight the importance of lysosomal degradation of proteins in human physiology and pathophysiology.

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

  • Research Products

    (2 results)

All 2020

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results) (of which Invited: 1 results)

  • [Journal Article] Cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes2020

    • Author(s)
      Hase Katsunori、Contu Viorica Raluca、Kabuta Chihana、Sakai Ryohei、Takahashi Masayuki、Kataoka Naoyuki、Hakuno Fumihiko、Takahashi Shin-Ichiro、Fujiwara Yuuki、Wada Keiji、Kabuta Tomohiro
    • Journal Title

      Autophagy

      Volume: 16 Pages: 1974~1988

    • DOI

      10.1080/15548627.2020.1712109

    • Peer Reviewed / Open Access
  • [Presentation] リソソームによる新しいタンパク質分解機構2020

    • Author(s)
      株田智弘
    • Organizer
      第93回日本生化学会大会
    • Invited

URL: 

Published: 2021-12-27  

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