摘要
Although numerous studies have shown that the proteinα-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 Ca^(2+),α-Syn can interact with synaptic vesicles,the mechanisms underlying that interaction are far from clear.Thus,we used single-vesicle imaging to quantify the extent to which Ca^(2+)regulates nanoscale vesicle clustering mediated by α-Syn.Our results revealed not only that vesicle clustering requiredα-Syn to bind to anionic lipid vesicles,but also that different concentrations of Ca^(2+)exerted different effects on howα-Syn induced vesicle clustering.In particular,low concentrations of Ca^(2+)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 Ca^(2+)and the negatively charged lipids that is independent of α-Syn.Taken together,our results provide critical insights intoα-Syn’s physiological function,and how Ca^(2+) regulates vesicle clustering mediated by α-Syn.
基金
We thank Dr.Chirlmin Joo for help in preparing the figure of the TIRFM setup and Dr.Tom Thompson for help with the CD experiments.B.B.,D.L.,L.Z.,W.D.,and B.J.were supported by funds from the National Natural Science Foundation of China(NSFC 11932017,11772054,11772055,11532009,11902051,and 31871031)
W.D.was supported by the Sichuan Science and Technology Program(2019YJ0481)
D.L.was supported by the Fundamental Research Funds for the Central Universities(Grant no.2019QNA4060)
J.D.was supported by the Michael J Fox Foundation(ID 16661).
