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.
Satra Nim  #  1 ,  Darren M O'Hara  #  2 ,  Carles Corbi-Verge  1 ,  Albert Perez-Riba  1 ,  Kazuko Fujisawa  2 ,  Minesh Kapadia  2 ,  Hien Chau  2 ,  Federica Albanese  2 ,  Grishma Pawar  2 ,  Mitchell L De Snoo  2 ,  Sophie G Ngana  2 ,  Jisun Kim  1 ,  Omar M A El-Agnaf  3 ,  Enrico Rennella  4 ,  Lewis E Kay  4  5  6  7 ,  Suneil K Kalia  #  8  9 ,  Lorraine V Kalia  #  10  11  12 ,  Philip M Kim  #  13  14  15
Affiliations
  • 1. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
  • 2. Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
  • 3. Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar.
  • 4. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 5. Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • 6. Department of Chemistry, University of Toronto, Toronto, ON, Canada.
  • 7. Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.
  • 8. Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. [email protected].
  • 9. Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada. [email protected].
  • 10. Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. [email protected].
  • 11. Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada. [email protected].
  • 12. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada. [email protected].
  • 13. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada. [email protected].
  • 14. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
  • 15. Department of Computer Science, University of Toronto, Toronto, ON, Canada. [email protected].
  • # Contributed equally.
PMID: 37076542 DOI: 10.1038/s41467-023-37464-2
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.

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