Distinct α-Synuclein:Lipid Co-Structure Complexes Affect Amyloid Nucleation through Fibril Mimetic Behavior

A hallmark of Parkinson's disease is the presence of Lewy bodies consisting of lipids and proteins, mainly fibrillated α-synuclein (aSN). aSN is an intrinsically disordered protein exerting its physiological role in an ensemble of states, one of which coexists in large assemblies with lipids, recently termed co-structures. Here, we decipher the kinetics of aSN:lipid co-structure formation to decode its mechanism of formation, and we show that the co-structures form with a distinct stoichiometry. Through seeded fibrillation assays, we demonstrate that aSN:lipid co-structures accelerate aSN fibril nucleation compared to lipid vesicles alone. A small-angle X-ray scattering-based model is proposed in which aSN decorates the lipid vesicle surface, yielding properties similar to those of the fibril surface, enhancing fibril nucleation. The delicate balance of aSN structural states close to and on the membrane may under given conditions, e.g., increased local concentrations, be a crucial switching factor between functional and pathological behavior.