BETA- AND GAMMA-SYNUCLEINS MODULATE SYNAPTIC VESICLE-BINDING OF ALPHA-SYNUCLEIN

Abstract

-Synuclein (Syn), {beta}-synuclein ({beta}Syn), and {gamma}-synuclein ({gamma}Syn) are abundantly expressed in the vertebrate nervous system. Syn functions in neurotransmitter release via binding to and clustering synaptic vesicles and chaperoning of SNARE-complex assembly. The functions of {beta}Syn and {gamma}Syn are unknown. Functional redundancy of the three synucleins and mutual compensation when one synuclein is deleted have been proposed, but with conflicting evidence. Here, we demonstrate that {beta}Syn and {gamma}Syn have a reduced affinity towards membranes compared to Syn, and that direct interaction of {beta}Syn or {gamma}Syn with Syn results in reduced membrane binding of Syn. Our data suggest that all three synucleins affect synapse function, but only Syn mediates the downstream function of vesicle clustering and SNARE-complex assembly, while {beta}Syn and {gamma}Syn modulate the activity of Syn through regulating its binding to synaptic vesicles.