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Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease

Author

Listed:
  • Satra Nim

    (University of Toronto)

  • Darren M. O’Hara

    (University Health Network)

  • Carles Corbi-Verge

    (University of Toronto)

  • Albert Perez-Riba

    (University of Toronto)

  • Kazuko Fujisawa

    (University Health Network)

  • Minesh Kapadia

    (University Health Network)

  • Hien Chau

    (University Health Network)

  • Federica Albanese

    (University Health Network)

  • Grishma Pawar

    (University Health Network)

  • Mitchell L. Snoo

    (University Health Network)

  • Sophie G. Ngana

    (University Health Network)

  • Jisun Kim

    (University of Toronto)

  • Omar M. A. El-Agnaf

    (Hamad Bin Khalifa University (HBKU), Qatar Foundation)

  • Enrico Rennella

    (University of Toronto)

  • Lewis E. Kay

    (University of Toronto
    University of Toronto
    University of Toronto
    The Hospital for Sick Children Research Institute)

  • Suneil K. Kalia

    (University Health Network
    University of Toronto)

  • Lorraine V. Kalia

    (University Health Network
    University of Toronto
    University of Toronto)

  • Philip M. Kim

    (University of Toronto
    University of Toronto
    University of Toronto)

Abstract

Accumulation of α-synuclein into toxic oligomers or fibrils is implicated in dopaminergic neurodegeneration in Parkinson’s disease. Here we performed a high-throughput, proteome-wide peptide screen to identify protein-protein interaction inhibitors that reduce α-synuclein oligomer levels and their associated cytotoxicity. We find that the most potent peptide inhibitor disrupts the direct interaction between the C-terminal region of α-synuclein and CHarged Multivesicular body Protein 2B (CHMP2B), a component of the Endosomal Sorting Complex Required for Transport-III (ESCRT-III). We show that α-synuclein impedes endolysosomal activity via this interaction, thereby inhibiting its own degradation. Conversely, the peptide inhibitor restores endolysosomal function and thereby decreases α-synuclein levels in multiple models, including female and male human cells harboring disease-causing α-synuclein mutations. Furthermore, the peptide inhibitor protects dopaminergic neurons from α-synuclein-mediated degeneration in hermaphroditic C. elegans and preclinical Parkinson’s disease models using female rats. Thus, the α-synuclein-CHMP2B interaction is a potential therapeutic target for neurodegenerative disorders.

Suggested Citation

  • Satra Nim & Darren M. O’Hara & Carles Corbi-Verge & Albert Perez-Riba & Kazuko Fujisawa & Minesh Kapadia & Hien Chau & Federica Albanese & Grishma Pawar & Mitchell L. Snoo & Sophie G. Ngana & Jisun Ki, 2023. "Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37464-2
    DOI: 10.1038/s41467-023-37464-2
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    References listed on IDEAS

    as
    1. Melissa D. Stuchell-Brereton & Jack J. Skalicky & Collin Kieffer & Mary Anne Karren & Sanaz Ghaffarian & Wesley I. Sundquist, 2007. "ESCRT-III recognition by VPS4 ATPases," Nature, Nature, vol. 449(7163), pages 740-744, October.
    2. Zhuohao He & Jennifer D. McBride & Hong Xu & Lakshmi Changolkar & Soo-jung Kim & Bin Zhang & Sneha Narasimhan & Garrett S. Gibbons & Jing L. Guo & Michael Kozak & Gerard D. Schellenberg & John Q. Troj, 2020. "Transmission of tauopathy strains is independent of their isoform composition," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    3. Etienne Morel & Zeina Chamoun & Zofia M. Lasiecka & Robin B. Chan & Rebecca L. Williamson & Christopher Vetanovetz & Claudia Dall’Armi & Sabrina Simoes & Kimberly S. Point Du Jour & Brian D. McCabe & , 2013. "Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system," Nature Communications, Nature, vol. 4(1), pages 1-13, October.
    4. Michael J. Devine & Mina Ryten & Petr Vodicka & Alison J. Thomson & Tom Burdon & Henry Houlden & Fatima Cavaleri & Masumi Nagano & Nicola J. Drummond & Jan-Willem Taanman & Anthony H. Schapira & Katri, 2011. "Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus," Nature Communications, Nature, vol. 2(1), pages 1-10, September.
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