Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2

Elife. 2013 Apr 30:2:e00592. doi: 10.7554/eLife.00592.


α-Synuclein is a presynaptic protein that is implicated in Parkinson's and other neurodegenerative diseases. Physiologically, native α-synuclein promotes presynaptic SNARE-complex assembly, but its molecular mechanism of action remains unknown. Here, we found that native α-synuclein promotes clustering of synaptic-vesicle mimics, using a single-vesicle optical microscopy system. This vesicle-clustering activity was observed for both recombinant and native α-synuclein purified from mouse brain. Clustering was dependent on specific interactions of native α-synuclein with both synaptobrevin-2/VAMP2 and anionic lipids. Out of the three familial Parkinson's disease-related point mutants of α-synuclein, only the lipid-binding deficient mutation A30P disrupted clustering, hinting at a possible loss of function phenotype for this mutant. α-Synuclein had little effect on Ca(2+)-triggered fusion in our reconstituted single-vesicle system, consistent with in vivo data. α-Synuclein may therefore lead to accumulation of synaptic vesicles at the active zone, providing a 'buffer' of synaptic vesicles, without affecting neurotransmitter release itself. DOI:

Keywords: Mouse; Parkinson's disease; alpha-synuclein; synaptic terminals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / isolation & purification
  • Animals
  • Brain / metabolism
  • Mice
  • Molecular Mimicry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / isolation & purification
  • Phospholipids / metabolism*
  • Synaptic Vesicles / metabolism*
  • Synaptotagmin I / genetics
  • Synaptotagmin I / isolation & purification
  • Vesicle-Associated Membrane Protein 2 / metabolism*
  • alpha-Synuclein / physiology*


  • Adaptor Proteins, Vesicular Transport
  • Nerve Tissue Proteins
  • Phospholipids
  • Synaptotagmin I
  • Syt1 protein, mouse
  • Vesicle-Associated Membrane Protein 2
  • alpha-Synuclein
  • complexin I