Cholesterol in Synaptic Vesicle Membranes Regulates the Vesicle-Binding, Function, and Aggregation of α-Synuclein

Loss of function and aggregation of the neuronal protein α-Synuclein (A-Syn) underlies the pathogenesis of Parkinson's disease (PD), and both the function and aggregation of this protein happen to be mediated via its binding to the synaptic vesicles (SVs) at the presynaptic termini. An essential constituent of SV membranes is cholesterol, with which A-Syn directly interacts while binding to membranes. Thus, cholesterol content in SV membranes is likely to affect the binding of A-Syn to these vesicles and consequently its functional and pathogenic behaviors. Interestingly, the dyshomeostasis of cholesterol has often been associated with PD, with reports linking both high and low cholesterol levels to an increased risk of neurodegeneration. Herein, using SV-mimicking liposomes containing increasing percentages of membrane cholesterol, we show (with mathematical interpretation) that the binding of A-Syn to synaptic-like vesicles is strongest in the presence of an optimum cholesterol content, which correlates to its maximum function and minimum aggregation. This implicates a minimum risk of neurodegeneration at optimum cholesterol levels and rationalizes the existing controversial relationship between cholesterol levels and PD. Increased membrane cholesterol was, however, found to protect against damage caused by aggregated A-Syn, complementing previous reports and portraying one advantage of high cholesterol over low.