The Role of a-Synuclein in SNARE-mediated Synaptic Vesicle Fusion

Neuronal communication depends on exquisitely regulated membrane fusion between synaptic vesicles and presynaptic neurons, which results in neurotransmitter release in precisely timed patterns. Presynaptic dysfunctions are known to occur prior to the onset of neurodegenerative diseases, including Parkinson's disease. Synaptic accumulation of a-synuclein (a-Syn) oligomers has been implicated in the pathway leading to such outcomes. a-Syn oligomers exert aberrant effects on presynaptic fusion machinery through their interactions with synaptic vesicles and proteins. Here, we summarize in vitro bulk and single-vesicle assays for investigating the functions of a-Syn monomers and oligomers in synaptic vesicle fusion and then discuss the current understanding of the roles of a-Syn monomers and oligomers in synaptic vesicle fusion. Finally, we suggest a new therapeutic avenue specifically targeting the mechanisms of a-Syn oligomer toxicity rather than the oligomer itself.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).