Dual Effects of Presynaptic Membrane Mimetics on alpha-Synuclein Amyloid Aggregation

Abstract

Aggregation of intrinsically disordered alpha-synuclein (alpha SN) under various conditions is closely related to synucleinopathies. Although various biological membranes have shown to alter the structure and aggregation propensity of alpha SN, a thorough understanding of the molecular and mechanical mechanism of amyloidogenesis in membranes remains unanswered. Herein, we examined the structural changes, binding properties, and amyloidogenicity of three variations of alpha SN mutants under two types of liposomes, 1,2-Dioleoyl-sn-glycero-3-Phosphocholine (DOPC) and presynaptic vesicle mimetic (Mimic) membranes. While neutrally charged DOPC membranes elicited marginal changes in the structure and amyloid fibrillation of alpha SNs, negatively charged Mimic membranes induced dramatic helical folding and biphasic amyloid generation. At low concentration of Mimic membranes, the amyloid fibrillation of alpha SNs was promoted in a dose-dependent manner. However, further increases in the concentration constrained the fibrillation process. These results suggest the dual effect of Mimic membranes on regulating the amyloidogenesis of alpha SN, which is rationalized by the amyloidogenic structure of alpha SN and condensation-dilution of local alpha SN concentration. Finally, we propose physicochemical properties of alpha SN and membrane surfaces, and their propensity to drive electrostatic interactions as decisive factors of amyloidogenesis.