Alpha-synuclein oligomers distinctively permeabilize model plasma and mitochondrial membranes

Alpha-synuclein (aS) oligomers are increasingly considered to be responsible for the death of dopaminergic neurons in Parkinson’s disease (PD). The toxicity mechanism of aS oligomers likely involves membrane permeabilization. Even though it is well-established that aS oligomers bind and permeabilize vesicles composed of negatively charged lipids, little attention has been given to the interaction of oligomers with bilayers of physiologically relevant lipid compositions. We demonstrate that aS binds to bilayers composed of lipid mixtures that mimic those of plasma and mitochondrial membranes. Circular dichroism experiments indicate that binding induces conformational changes in both oligomeric and monomeric aS. The membrane leakage that results from oligomer binding to physiologically relevant membranes differs from that observed for simple artificial model bilayers. Instead of inducing fast content release, oligomer binding increases the permeability of artificial mitochondrial membranes resulting in a slow loss of content. Oligomers are not able to induce leakage in artificial plasma membranes even after long-term incubation. The results uggest that the mitochondrial membrane is th