Alpha-Synuclein Continues to Enhance SNARE-Dependent Vesicle Docking at Exorbitant Concentrations

Recently, Parkinson's disease-associated proportional to-synuclein (proportional to S) has emerged as an important regulator for SNARE-dependent vesicle fusion. However, it is controversial if excessive accumulation of proportional to S, even in the absence of aggregation, impairs neurotransmission. Here we use a single vesicle fusion assay with ms time resolution capable of dissecting the impact of proportional to S on each step of membrane fusion. Unlike the previous results from various in vitro, cellular, and in vivo studies, we find that non-aggregated proportional to S promotes vesicle merger even at exorbitant concentrations. The enhancement has been seen as much as 13 fold. Delving into the kinetics of the intermediate states for vesicle fusion reveals that proportional to S stimulates vesicle docking without altering the dynamics of bilayer merger (lipid mixing). However, minute amounts of soluble aggregated species abolish SNARE-dependent bilayer merger completely. Thus, the results show that excessive accumulation of non-aggregated proportional to S may not be toxic for neurotransmitter release.