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

Nat Commun. 2023 Apr 19;14(1):2150. doi: 10.1038/s41467-023-37464-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / metabolism
  • Dopaminergic Neurons / metabolism
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Female
  • Humans
  • Male
  • Parkinson Disease* / drug therapy
  • Parkinson Disease* / metabolism
  • Peptides / metabolism
  • Peptides / pharmacology
  • Rats
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism


  • alpha-Synuclein
  • Endosomal Sorting Complexes Required for Transport
  • Peptides