α-Synuclein Multimers Cluster Synaptic Vesicles and Attenuate Recycling
Abstract
Summary. 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.
- Publication:
-
Current Biology
- Pub Date:
- October 2014
- DOI:
- 10.1016/j.cub.2014.08.027
- Bibcode:
- 2014CBio...24.2319W