Influence of Cholesterol on the Membrane Binding and Conformation of α-Synuclein

The α-Synuclein (α-Syn) plays an important role in the pathology of Parkinson's disease (PD), and its oligomers and fibrils are toxic to the nervous system. As organisms age, the cholesterol content in biological membranes increases, which is a potential cause of PD. Cholesterol may affect the membrane binding of α-Syn and its abnormal aggregation, but the mechanism remains unclear. Here, we present our molecular dynamics simulation studies on the interaction between α-Syn and lipid membranes, with or without cholesterol. It is demonstrated that cholesterol provides additional hydrogen bond interaction with α-Syn; however, the coulomb interaction and hydrophobic interaction between α-Syn and lipid membranes could be weakened by cholesterol. In addition, cholesterol leads to the shrinking of lipid packing defects and the decrease of lipid fluidity, thereby shortening the membrane binding region of α-Syn. Under these multifaceted effects of cholesterol, membrane-bound α-Syn shows signs of forming a β-sheet structure, which may further induce the formation of abnormal α-Syn fibrils. These results provide important information for the understanding of membrane binding of α-Syn, and they are expected to promote the bridging between cholesterol and the pathological aggregation of α-Syn.