α-Synuclein multimers cluster synaptic vesicles and attenuate recycling

Lina Wang, Utpal Das, David A. Scott, Yong Tang, Pamela J. McLean, Subhojit Roy

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

The normal functions and pathologic facets of the small presynaptic protein α-synuclein (α-syn) are of exceptional interest. In previous studies, we found that α-syn attenuates synaptic exo/endocytosis [1, 2]; however, underlying mechanisms remain unknown. More recent evidence suggests that α-syn exists as metastable multimers and not solely as a natively unfolded monomer [3-8]. However, conformations of α-syn at synapses - its physiologic locale - are unclear, and potential implications of such higher-order conformations to synaptic function are unknown. Exploring α-syn conformations and synaptic function in neurons, we found that α-syn promptly organizes into physiological multimers at synapses. Furthermore, our experiments indicate that α-syn multimers cluster synaptic vesicles and restrict their motility, suggesting a novel role for these higher-order structures. Supporting this, α-syn mutations that disrupt multimerization also fail to restrict synaptic vesicle motility or attenuate exo/endocytosis. We propose a model in which α-syn multimers cluster synaptic vesicles, restricting their trafficking and recycling, and consequently attenuate neurotransmitter release.

Original languageEnglish (US)
Pages (from-to)2319-2326
Number of pages8
JournalCurrent Biology
Volume24
Issue number19
DOIs
StatePublished - Oct 6 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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