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

• Published in: Journal of molecular biology 2023-01, Vol.435 (1), p.167714, Article 167714
• Main Authors: Gao, Virginia, Briano, Juan A., Komer, Lauren E., Burré, Jacqueline
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Humans; membrane binding; neuronal survival; neurotransmitter release; Parkinson Disease - metabolism; Parkinson’s disease; SNARE Proteins - metabolism; Synapses - metabolism; synaptic vesicle; Synaptic Vesicles - metabolism; Vesicle-Associated Membrane Protein 2 - metabolism
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2022.167714

[Display omitted] •α-Synuclein functions through its membrane-bound state on synaptic vesicles.•α-Synuclein chaperones SNARE complex assembly via binding to VAMP2/synaptobrevin-2.•α-Synuclein clusters synaptic vesicles to modulate vesicle pools.•α-Synuclein membrane-binding is neuroprotective in physiological states.•α-Synuclein is important for long-term neuronal function. α-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 diseases now known as the synucleinopathies. Physiologically, α-synuclein exists in an equilibrium between a synaptic vesicle membrane-bound α-helical multimer and a cytosolic largely unstructured monomer. Through its membrane-bound state, α-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 α-synuclein’s interactions with the synaptic vesicle SNARE protein VAMP2/synaptobrevin-2, the synaptic vesicle-attached synapsins, and the synaptic vesicle membrane itself. How α-synuclein affects these processes, and whether disease is due to loss-of-function or gain-of-toxic-function of α-synuclein remains unclear. In this review, we provide an in-depth summary of the existing literature, discuss possible reasons for the discrepancies in the field, and propose a working model that reconciles the findings in the literature.