Synucleins in Neural Physiology: Understanding Endogenous Function to Better Contextualize Pathology

Perhaps most well-known for its penetrant role in synucleinopathies, alpha-synuclein's nonpathological function remains incompletely characterized. Most widely regarded as a putative presynaptic protein, a growing body of work over the last few decades demonstrates that alpha-synuclein participates in a broad and more diverse set of neuronal functions. Alpha-synuclein is a small, intrinsically disordered protein comprising three functionally distinct regions that mediate membrane binding, vesicle clustering, and protein-protein interactions. At synapses, alpha-synuclein participates in multiple steps of neurotransmission, including organization of the vesicle reserve pool, recruitment of release machinery, and recycling of synaptic vesicles. Emerging evidence further supports roles for alpha-synuclein beyond classical presynaptic compartments, including interactions with nonsynaptic membranes and secretion via extracellular vesicles. This review aims to integrate the literature on alpha-synuclein's structure and function to better underscore how these properties may contribute to vulnerability in disease when these normal functions are lost.