Abstract

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+, 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 Ca2+ regulates nanoscale vesicle clustering mediated by α-Syn. Our results revealed not only that vesicle clustering required α-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.

Highlights

  • Introduction αSynuclein (α-Syn), a presynaptic protein abundantly expressed throughout the central nervous system, is the hallmark of Parkinson’s disease, dementia with Lewy bodies, and other neurodegenerative diseases[1,2]

  • Our results provide critical insights into αSyn’s physiological function and the mechanism by which calcium ions regulate vesicle clustering mediated by α-Syn

  • Conclusion α-Syn has been shown to interact with isolated synaptic vesicles via its vesicle-binding domain, which results in the clustering of synaptic vesicles, and Ca2+ can regulate vesicle clustering mediated by α-Syn

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Summary

Introduction

Introduction αSynuclein (α-Syn), a presynaptic protein abundantly expressed throughout the central nervous system, is the hallmark of Parkinson’s disease, dementia with Lewy bodies, and other neurodegenerative diseases[1,2]. Recent studies have indicated that α-Syn binds to the highly curved membranes of synaptic vesicles, and senses and regulates the curvature of those membranes, which. Α-Syn is an intrinsically disordered protein that binds to small synaptic vesicles via a conserved lipid-binding domain. When binding to a lipid membrane, the N terminus of α-Syn forms either an extended helix structure or two broken structures[13,14]. It has been proposed that α-Syn acts as a bridge between membranes—for example, that two helices each bind to two different synaptic vesicles—the result of which is vesicle clustering[15]. Recent studies have suggested that calcium ions (Ca2+) can mediate the interaction between α-Syn and lipid membranes.

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