Tipping point in α-synuclein-membrane interactions from stable protein-covered vesicles to amyloid aggregation

α-synuclein is a neuronal protein implicated in neurotransmitter release. Its function is thought to critically depend on the dynamic equilibrium between its free and its membrane-bound state. α-synuclein amyloid formation, implicated in Parkinson's disease, is also modulated by lipid membranes. The interplay between these processes remains elusive yet relates to the outstanding question of what determines the switch between physiological and disease-related behavior of the protein. Here, we study the coupling of equilibrium between free and membrane-bound α-synuclein and membrane-induced amyloid formation at lipid-to-protein ratios where amyloid formation is either accelerated or inhibited by lipid membranes. We find a clear difference between the exchange dynamics and the heterogeneity of the protein-covered membrane interface under these two sets of conditions. Our results highlight a strong coupling of membrane-modulated amyloid formation and the equilibrium between free and membrane-bound α-synuclein, which advances our molecular understanding of the physiological function of α-synuclein and its aberrant aggregation.