Helical α-Synuclein Forms Highly Conductive Ion Channels†

α-Synuclein (αS) is a cytosolic protein involved in the etiology of Parkinson's disease (PD). Disordered in an aqueous environment, αS develops a highly helical conformation when bound to membranes having a negatively charged surface and a large curvature. It exhibits a membrane-permeabilizing activity that has been attributed to oligomeric protofibrillar forms. In this study, monomeric wild-type αS and two mutants associated with familial PD, E46K and A53T, formed ion channels with well-defined conductance states in membranes containing 25−50% anionic lipid and 50% phosphatidylethanolamine (PE) in the presence of a trans-negative potential. Another familial mutant, A30P, known to have a lower membrane affinity, did not form ion channels. Ca2+ prevented channel formation when added to membranes before αS and decreased channel conductance when added to preformed channels. In contrast to the monomer, membrane permeabilization by oligomeric αS was not characterized by formation of discrete channels, a requir...