VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates

Nat Cell Biol. 2024 Aug;26(8):1287-1295. doi: 10.1038/s41556-024-01456-1. Epub 2024 Jul 1.

Abstract

α-Synuclein (α-Syn) aggregation is closely associated with Parkinson's disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)-a component of the SNARE complex that resides on SVs-directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn's function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn's function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson's disease.

MeSH terms

  • Animals
  • Humans
  • Mice
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Protein Binding
  • Rats
  • SNARE Proteins / genetics
  • SNARE Proteins / metabolism
  • Synaptic Vesicles* / metabolism
  • Vesicle-Associated Membrane Protein 2* / genetics
  • Vesicle-Associated Membrane Protein 2* / metabolism
  • alpha-Synuclein* / genetics
  • alpha-Synuclein* / metabolism

Substances

  • alpha-Synuclein
  • Vesicle-Associated Membrane Protein 2
  • VAMP2 protein, human
  • SNARE Proteins
  • Molecular Chaperones
  • vesicle-associated membrane protein 2, mouse