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Alpha synuclein (αS) is a ~14 kDa intrinsically disordered protein with a yet unknown physiological function. The conversion of monomeric αS into amyloid aggregates is believed to play a central role of the pathology of Parkinson’s disease (PD). Despite extensive studies on amyloid formation of αS in bulk solution, the mechanistic details of αS aggregation at biological interfaces like lipid membranes are unclear. Further, it is also unknown how amyloid aggregates that are formed in PD potentiate neuronal cell death. Association with (specific) cellular membranes is believed facilitate amyloid formation, but this hypothesis is clouded by the fact that the physiological function of αS probably also involves association with physiological cell membranes. Therefore, understanding interactions of αS with lipid membranes is critical to uncover its possible functional or pathological role, which we have investigated in this thesis. In particular, we focus on the following questions which form the core of the thesis: * How are physical properties of phospholipid membranes affected by αS binding and aggregation and vice versa? * How do early amyloid aggregates of αS perturb phospholipid membranes? * What is the role of N-terminal acetylation in αS on its membrane binding properties and aggregation propensities? * How do terminal domains in αS affect the morphology of amyloid aggregates? To answer these questions a wide range of biochemical and biophysical techniques like fluorescence confocal microscopy, fluorescence anisotropy, circular dichroism, Fourier transform infra-red spectroscopy and fluorescence recovery after photobleaching were used to probe the interactions of lipid membranes with monomeric αS. Our results show the importance of inter-αS, inter-lipid and αS–lipid interactions that are involved both prior to and post amyloid formation

The many faces of alpha synuclein: from phospholipid bilayer interactions to amyloid aggregation