Functional analysis of oligomeric alpha-synuclein in membrane permeabilization

Parkinson's disease is a common neurodegenerative disorder marked by increased cell death within the substantia nigra pars compacta. It is characterized by the presence of intracellular aggregates composed primarily of the protein alpha-synuclein. How the aggregation of a-synuclein is related to neuronal degeneration is an important unresolved question. Oligomeric intermediates have been found to be more toxic to cells than monomeric or fibrillar forms of the protein. A possible mechanism by which oligomers could be toxic is through the disruption and permeabilization of cellular membranes. The proposed disruption mechanism is the formation of pore-like structures within the lipid bilayer although this mechanism is still highly controversial. To identify the mechanism through which membrane permeabilization is facilitated and to estimate the biological relevance of this process, it is crucial to have a greater knowledge of the lipid-oligomer interaction. The membrane disruptive effect of Alpha-synuclein oligomers on lipid vesicles of different headgroup composition using the ANTS/DPX assay was evaluated in this work. It was shown that membrane permeabilization is mainly determined by the presence of negatively charged lipids and also by lipid packing parameters, suggesting that the accessibility to the bilayer hydrocarbon core modulates oligomer-membrane interaction.