α-Synuclein Multimers Cluster Synaptic Vesicles and Attenuate Recycling

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