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

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 Kim, Omar M. A. El-Agnaf, Enrico Rennella, Lewis E. Kay, Suneil K. Kalia (), Lorraine V. Kalia () and Philip M. Kim ()
Additional contact information
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
Suneil K. Kalia: University Health Network
Lorraine V. Kalia: University Health Network
Philip M. Kim: University of Toronto

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37464-2

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