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Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance

Author

Listed:
  • Lidia Wrobel

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Sandra M. Hill

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus
    The Sahlgrenska Academy at the University of Gothenburg)

  • Alvin Djajadikerta

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Marian Fernandez-Estevez

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Cansu Karabiyik

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Avraham Ashkenazi

    (Cambridge Biomedical Campus)

  • Victoria J. Barratt

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Eleanna Stamatakou

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Anders Gunnarsson

    (Biophysics SE, Discovery Sciences, R&D, AstraZeneca)

  • Timothy Rasmusson

    (Discovery Biology, Discovery Sciences, R&D, AstraZeneca)

  • Eric W. Miele

    (Discovery Biology, Discovery Sciences, R&D, AstraZeneca)

  • Nigel Beaton

    (Biognosys AG)

  • Roland Bruderer

    (Biognosys AG)

  • Yuehan Feng

    (Biognosys AG)

  • Lukas Reiter

    (Biognosys AG)

  • M. Paola Castaldi

    (Discovery Biology, Discovery Sciences, R&D, AstraZeneca)

  • Rebecca Jarvis

    (Discovery UK, Neuroscience, BioPharmaceuticals R&D, AstraZeneca)

  • Keith Tan

    (Discovery UK, Neuroscience, BioPharmaceuticals R&D, AstraZeneca)

  • Roland W. Bürli

    (Discovery UK, Neuroscience, BioPharmaceuticals R&D, AstraZeneca)

  • David C. Rubinsztein

    (Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

Abstract

Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington’s disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome. Here we find that compounds that activate the D1 ATPase activity of VCP/p97 fulfill these requirements. Such effects are seen with small molecule VCP activators like SMER28, which activate autophagosome biogenesis by enhancing interactions of PI3K complex components to increase PI(3)P production, and also accelerate VCP-dependent proteasomal clearance of such substrates. Thus, this mode of VCP activation may be a very attractive target for many neurodegenerative diseases.

Suggested Citation

  • Lidia Wrobel & Sandra M. Hill & Alvin Djajadikerta & Marian Fernandez-Estevez & Cansu Karabiyik & Avraham Ashkenazi & Victoria J. Barratt & Eleanna Stamatakou & Anders Gunnarsson & Timothy Rasmusson &, 2022. "Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31905-0
    DOI: 10.1038/s41467-022-31905-0
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    References listed on IDEAS

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    1. Noboru Mizushima & Takeshi Noda & Tamotsu Yoshimori & Yae Tanaka & Tomoko Ishii & Michael D. George & Daniel J. Klionsky & Mariko Ohsumi & Yoshinori Ohsumi, 1998. "A protein conjugation system essential for autophagy," Nature, Nature, vol. 395(6700), pages 395-398, September.
    2. Avraham Ashkenazi & Carla F. Bento & Thomas Ricketts & Mariella Vicinanza & Farah Siddiqi & Mariana Pavel & Ferdinando Squitieri & Maarten C. Hardenberg & Sara Imarisio & Fiona M. Menzies & David C. R, 2017. "Polyglutamine tracts regulate beclin 1-dependent autophagy," Nature, Nature, vol. 545(7652), pages 108-111, May.
    3. Ilaria Piazza & Nigel Beaton & Roland Bruderer & Thomas Knobloch & Crystel Barbisan & Lucie Chandat & Alexander Sudau & Isabella Siepe & Oliver Rinner & Natalie de Souza & Paola Picotti & Lukas Reiter, 2020. "A machine learning-based chemoproteomic approach to identify drug targets and binding sites in complex proteomes," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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