?-synuclein multimers cluster synaptic vesicles and attenuate recycling.

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

SUBMITTER: Wang L 

PROVIDER: S-EPMC4190006 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature