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

Abstract

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.

Biologically Representative Lipid-Coated Gold Nanoparticles and Phospholipid Vesicles for the Study of Alpha-Synuclein/Membrane Interactions

“…Interestingly, the association constants for the current lipid-coated gold nanoparticle mimics are roughly 1–2 orders of magnitude higher than those of previously studied sodium dodecyl sulfate coated gold nanoparticles and citrate-capped gold nanoparticles analyzed by the same approach (Table ). This increased affinity could be a result of packing defects and grain boundaries arising in the more complex, mixed lipid surface chemistry, as previous studies have suggested that alpha-synuclein exhibits heightened affinity for such defects in lipid bilayers. ,, However, factors such as ionic strength, pH, and temperature can also impact protein binding affinities − and should be considered as a point of caution when comparing results across multiple studies conducted under different experimental conditions, even when the same method of analysis was applied.…”

“…This increased affinity could be a result of packing defects and grain boundaries arising in the more complex, mixed lipid surface chemistry, as previous studies have suggested that alpha-synuclein exhibits heightened affinity for such defects in lipid bilayers. 22,44,45 However, factors such as ionic strength, pH, and temperature can also impact protein binding affinities 46−48 and should be considered as a point of caution when comparing results across multiple studies conducted under different experimental conditions, even when the same method of analysis was applied.…”

“…32 Comparing just our small phospholipid vesicle conditions, we observe a trend similar to that reported by Mahapatra et al in which addition of cholesterol results in an increase in binding affinity. Interestingly, we do not observe a trend in either direction for the large phospholipid vesicle samples, suggesting that the ability of cholesterol content to influence binding affinity, possibly through modulating lipid packing defects, 44,45 is less significant for larger vesicles with lower surface curvature.…”

The cholesterol 24-hydroxylase enzyme, CYP46A1, reduces overexpressed alpha-synuclein proteins in human cellular models of Parkinson’s disease.

“…Recent ndings indicate that Lewy bodies in addition of the high level of alpha-syn proteins are also characterized by a high lipid content and degenerated organelles suggesting that lipids, which are the main constituents of cell membranes, may contribute to the development of the disease (Shahmoradian et al, 2019;Mahul-Mellier et al, 2020). Over the last two decades, accumulating evidence suggests a transient binding of alpha-syn to lipid membranes particularly in cholesterol-rich regions (Fortin et al, 2004;van Maarschalkerweerd et al, 2015;Kachappilly et al, 2022;Qi et al, 2023). Cholesterol may affect the binding of alpha-syn to the membrane and its abnormal aggregation (Man et al, 2020;Jakubec et al, 2021;Qi et al, 2023).…”

“…Over the last two decades, accumulating evidence suggests a transient binding of alpha-syn to lipid membranes particularly in cholesterol-rich regions (Fortin et al, 2004;van Maarschalkerweerd et al, 2015;Kachappilly et al, 2022;Qi et al, 2023). Cholesterol may affect the binding of alpha-syn to the membrane and its abnormal aggregation (Man et al, 2020;Jakubec et al, 2021;Qi et al, 2023). Studies have also demonstrated that alpha-syn signi cantly stimulates cholesterol e ux (Hsiao et al, 2017).…”