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

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

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. suneil.kalia@utoronto.ca.
  • 9 Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada. suneil.kalia@utoronto.ca.
  • 10 Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. lorraine.kalia@utoronto.ca.
  • 11 Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada. lorraine.kalia@utoronto.ca.
  • 12 Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada. lorraine.kalia@utoronto.ca.
  • 13 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada. pi@kimlab.org.
  • 14 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. pi@kimlab.org.
  • 15 Department of Computer Science, University of Toronto, Toronto, ON, Canada. pi@kimlab.org.
  • # 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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