1. Cell Biology

Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease

  1. Yuki Date
  2. Yukiko Sasazawa
  3. Mitsuhiro Kitagawa
  4. Kentaro Gejima
  5. Ayami Suzuki
  6. Hideyuki Saya
  7. yasuyuki kida
  8. Masaya Imoto
  9. Eisuke Itakura
  10. Nobutaka Hattori  Is a corresponding author
  11. Shinji Saiki  Is a corresponding author
  1. Chiba University, Japan
  2. Juntendo University, Japan
  3. Keio University, Japan
  4. National Institute of Advanced Industrial Science and Technology, Japan
  5. University of Tsukuba, Japan
https://doi.org/10.7554/eLife.98649
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  1. Yuki Date
  2. Yukiko Sasazawa
  3. Mitsuhiro Kitagawa
  4. Kentaro Gejima
  5. Ayami Suzuki
  6. Hideyuki Saya
  7. yasuyuki kida
  8. Masaya Imoto
  9. Eisuke Itakura
  10. Nobutaka Hattori
  11. Shinji Saiki
(2024)
Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease
eLife 13:e98649.
https://doi.org/10.7554/eLife.98649
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Abstract

The autophagy-lysosome pathway plays an indispensable role in the protein quality control by degrading abnormal organelles and proteins including a-synuclein (aSyn) associated with the pathogenesis of Parkinson's disease (PD). However, the activation of this pathway is mainly by targeting lysosomal enzymic activity. Here, we focused on the autophagosome-lysosome fusion process around the microtubule-organizing center (MTOC) regulated by lysosomal positioning. Through high-throughput chemical screening, we identified 6 out of 1,200 clinically approved drugs enabling the lysosomes to accumulate around the MTOC with autophagy flux enhancement. We further demonstrated that these compounds induce the lysosomal clustering through a JIP4-TRPML1-dependent mechanism. Among them, the lysosomal-clustering compound albendazole promoted the autophagy-dependent degradation of Triton-X-insoluble, proteasome inhibitor-induced aggregates. In a cellular PD model, albendazole boosted insoluble aSyn degradation. Our results revealed that lysosomal clustering can facilitate the breakdown of protein aggregates, suggesting that lysosome-clustering compounds may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.

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All data generated or analysed during this study are included in the manuscript and supporting files

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Author details

  1. Yuki Date

    Department of Biology, Chiba University, Chiba, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0009-0004-1099-1829

  2. Yukiko Sasazawa

    Department of Neurology, Juntendo University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0287-273X

  3. Mitsuhiro Kitagawa

    Department of Neurology, Juntendo University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Kentaro Gejima

    Department of Neurology, Juntendo University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. Ayami Suzuki

    Department of Neurology, Juntendo University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  6. Hideyuki Saya

    Division of Gene Regulation, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  7. yasuyuki kida

    Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan
    Competing interests
    The authors declare that no competing interests exist.

  8. Masaya Imoto

    Division for Development of Autophagy Modulating Drugs, Juntendo University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.

  9. Eisuke Itakura

    Department of Biology, Chiba University, Chiba, Japan
    Competing interests
    The authors declare that no competing interests exist.

  10. Nobutaka Hattori

    Department of Neurology, Juntendo University, Tokyo, Japan
    For correspondence
    nhattori@juntendo.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2305-301X

  11. Shinji Saiki

    Department of Neurology, University of Tsukuba, Tsukuba, Japan
    For correspondence
    ssaiki@md.tsukuba.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9732-8488

Funding

Japan Society for the Promotion of Science London (18K15464 21K07425)

  • Yukiko Sasazawa

Japan Society for the Promotion of Science London (18KK0242 18KT0027 22H02986)

  • Shinji Saiki

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2024, Date et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yuki Date
  2. Yukiko Sasazawa
  3. Mitsuhiro Kitagawa
  4. Kentaro Gejima
  5. Ayami Suzuki
  6. Hideyuki Saya
  7. yasuyuki kida
  8. Masaya Imoto
  9. Eisuke Itakura
  10. Nobutaka Hattori
  11. Shinji Saiki
(2024)
Novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease
eLife 13:e98649.
https://doi.org/10.7554/eLife.98649

Share this article

https://doi.org/10.7554/eLife.98649

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