Although numerous studies have shown that the protein α-synuclein (α-Syn) plays a central role in Parkinson's disease,dementia with Lewy bodies,and other neurodegenerative diseases,the protein's physiological function remains poorly understood.Furthermore,despite recent reports suggesting that,under the influence of Ca2+,cα-Syn can interact with synaptic vesicles,the mechanisms underlying that interaction are far from clear.Thus,we used singlevesicle imaging to quantify the extent to which Ca2+ regulates nanoscale vesicle clustering mediated by α-Syn.Our results revealed not only that vesicle clustering required cα-Syn to bind to anionic lipid vesicles,but also that different concentrations of Ca2+ exerted different effects on how α-Syn induced vesicle clustering.In particular,low concentrations of Ca2+ inhibited vesicle clustering by blocking the electrostatic interaction between the lipid membrane and the N terminus of α-Syn,whereas high concentrations promoted vesicle clustering,possibly due to the electrostatic interaction between Ca2+ and the negatively charged lipids that is independent of α-Syn.Taken together,our results provide critical insights into α-Syn's physiological function,and how Ca2+ regulates vesicle clustering mediated by α-Syn.
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