Membrane binding of oligomeric α-synuclein depends on bilayer charge and packing

Membrane disruption by oligomeric alpha-synuclein (alpha S) is considered a likely mechanism of cytotoxicity in Parkinson's disease (PD). However, the mechanism of oligomer binding and the relation between binding and membrane disruption is not known. We have visualized alpha S oligomer-lipid binding by fluorescence microscopy and have measured membrane disruption using a dye release assay. The data reveal that oligomeric alpha S selectively binds to membranes containing anionic lipids and preferentially accumulates into liquid disordered (Ld) domains. Furthermore, we show that binding of oligomers to the membrane and disruption of the membrane require different lipid properties. Thus membrane-bound oligomeric alpha S does not always cause bilayer disruption. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.