Functional and Pathological Effects of a-Synuclein on Synaptic SNARE Complexes

a-Synuclein is an abundant protein at the neuronal synapse that has been implicated in Parkinson's disease for over 25 years and characterizes the hallmark pathology of a group of neurodegenerative dis-eases now known as the synucleinopathies. Physiologically, a-synuclein exists in an equilibrium between a synaptic vesicle membrane-bound a-helical multimer and a cytosolic largely unstructured monomer. Through its membrane-bound state, a-synuclein functions in neurotransmitter release by modulating several steps in the synaptic vesicle cycle, including synaptic vesicle clustering and docking, SNARE complex assembly, and homeostasis of synaptic vesicle pools. These functions have been ascribed to a-synuclein's interactions with the synaptic vesicle SNARE protein VAMP2/synaptobrevin-2, the synaptic vesicle-attached synapsins, and the synaptic vesicle membrane itself. How a-synuclein affects these pro-cesses, and whether disease is due to loss-of-function or gain-of-toxic-function of a-synuclein remains unclear. In this review, we provide an in-depth summary of the existing literature, discuss possible rea-sons for the discrepancies in the field, and propose a working model that reconciles the findings in the literature.(c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

Alpha-synuclein is a protein that is abundant at the neuronal synapse and has been implicated in Parkinson's disease for over 25 years. It plays a role in neurotransmitter release by regulating various steps in the synaptic vesicle cycle. The exact mechanism of how alpha-synuclein affects these processes and its role in disease development remains unclear.