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Parkinson's disease is a neurodegenerative disease common with old age. The neuronal protein α-synuclein is considered to play a pivotal role in the onset and progression of the disease. The protein is the main constituent of the Lewy body, the pathological hallmark of the disease, which are large intracellular inclusion bodies that contain aggregated fibrillar protein. In addition mutations in the gene coding for the protein as well as gene multiplications lead to genetic variants of Parkinson's disease. One of the main questions is how the aggregation of α-synuclein is related to the disease. Recent evidence suggests that oligomeric intermediates in the aggregation process of α-synuclein are potentially the neurotoxic species that underlie the disease. A potential mechanism by which these could be toxic is through interaction and disruption of cellular membranes. In this thesis, we try to elucidate how oligomeric α-synuclein interacts with lipid membranes. This interaction was characterized using a number of biophysical techniques using synthetic lipid bilayer systems and recombinantly expressed α-synuclein. Stable off-pathway α-synuclein oligomers were prepared that bound and permeabilized vesicles composed of negatively charged lipids. The lipid binding is mediated by the positively charged N-terminus of the protein. The oligomers contain structural features that cause them to have a destabilizing effect on lipid membranes. Bilayer permeabilization most likely occurs through the formation of defects in the membrane

Structural and functional insights into interactions of oligomeric (alpha)-synuclein with lipid membranes