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Curr Biol. 2014 Oct 6;24(19):2319-26. doi: 10.1016/j.cub.2014.08.027. Epub 2014 Sep 25.

α-synuclein multimers cluster synaptic vesicles and attenuate recycling.

Author information

1
Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2
McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
4
Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: s1roy@ucsd.edu.

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; however, underlying mechanisms remain unknown. More recent evidence suggests that α-syn exists as metastable multimers and not solely as a natively unfolded monomer. 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.

PMID:
25264250
PMCID:
PMC4190006
DOI:
10.1016/j.cub.2014.08.027
[Indexed for MEDLINE]
Free PMC Article

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