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- Title
Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson's disease.
- Authors
Nim, Satra; O'Hara, Darren M.; Corbi-Verge, Carles; Perez-Riba, Albert; Fujisawa, Kazuko; Kapadia, Minesh; Chau, Hien; Albanese, Federica; Pawar, Grishma; De Snoo, Mitchell L.; Ngana, Sophie G.; Kim, Jisun; El-Agnaf, Omar M. A.; Rennella, Enrico; Kay, Lewis E.; Kalia, Suneil K.; Kalia, Lorraine V.; Kim, Philip M.
- 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. ESCRT-III is involved in the endolysosomal system and disturbed in neurodegenerative diseases. Here the authors show that disruption of an interaction between ESCRT-III member CHMP2B and α-synuclein by a peptide inhibitor mitigates neurodegeneration in Parkinson's disease models.
- Subjects
PEPTIDES; PARKINSON'S disease; DOPAMINERGIC neurons; ANIMAL models in research; ALPHA-synuclein; PROTEIN-protein interactions; NEURODEGENERATION
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-37464-2