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

Abstract 

Membrane disruption by oligomeric α-synuclein (αS) 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 αS oligomer-lipid binding by fluorescence microscopy and have measured membrane disruption using a dye release assay. The data reveal that oligomeric αS 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 αS does not always cause bilayer disruption.

Abbreviations: αS, α-synuclein, PD, Parkinson’s disease, Ld, liquid disordered, Lo, liquid ordered, GUVs, giant unilamellar vesicles, LUVs, large unilamellar vesicles, wt, wild-type, AL488, Alexa 488, POPC, 1-palmitoyl, 2-oleoyl phosphatidylcholine, POPG, 1-palmitoyl, 2-oleoyl phosphatidylglycerol, DPPG, 1,2-dipalmitoyl phosphatidylglycerol, 18:2-PG, 1,2-dilinoleoyl phosphatidylglycerol, POPS, 1-palmitoyl, 2-oleoyl phosphatidylserine, DOPA, 1,2-dioleoyl phosphatidic acid, DOPE-Rhod, 1,2-dioleoyl phosphatidylethanolamine-(lissamine rhodamine B), Chol, cholesterol

Keywords: Amyloid, Synuclein, Parkinson’s disease, Lipid, Pore, Confocal fluorescence microscopy