Alpha-Synuclein Oligomers Induced By Docosahexaenoic Acid Affect Membrane Integrity

A key feature of Parkinson disease is the aggregation of alpha-synuclein and its intracellular deposition in fibrillar form. Increasing evidence suggests that the pathogenicity of alpha-synuclein is correlated with the activity of oligomers formed in the early stages of its aggregation process. Oligomers toxicity seems to be associated with both their ability to bind and affect the integrity of lipid membranes. Previously, we demonstrated that alpha-synuclein forms oligomeric species in the presence of docosahexaenoic acid and that these species are toxic to cells. Here we studied how interaction of these oligomers with membranes results in cell toxicity, using cellular membrane-mimetic and cell model systems. We found that alpha-synuclein oligomers are able to interact with large and small unilamellar negatively charged vesicles acquiring an increased amount of alpha-helical structure, which induces small molecules release. We explored the possibility that oligomers effects on membranes could be due to pore formation, to a detergent-like effect or to fibril growth on the membrane. Our biophysical and cellular findings are consistent with a model where alpha-synuclein oligomers are embedded into the lipid bilayer causing transient alteration of membrane permeability.