Biophysical determination of the underlying cause of alpha-Syn oligomer toxicity.

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ABSTRACT Parkinson disease (PD) is the second most common neurodegenerative disease that affects nearly 5 millions of people around the world. PD is associated with intracellular aggregation of α-synuclein (α-Syn), a small protein that is involved in the regulation of lipid metabolism and synaptic vesicle trafficking. A growing body of evidence suggests that alterations in lipid profile, which were observed in both brain and plasma, can be directly linked to the onset of α-Syn aggregation. We hypothesize that the toxicity of α-Syn aggregates is determined by their structure, which in turn is controlled by the lipid composition of neuronal membranes. Our group pioneered development of a label-free, non-invasive and non-destructive approach that can be used to determine the structural organization of individual α-Syn aggregates. We will use this innovative biophysical imaging approach to unravel protein secondary structure of α-Syn oligomers grown in the presence of different lipids. We will investigate toxicity of these oligomers on primary dopaminergic neurons from midbrain, striatal, and cortical areas of the mouse brains. This will reveal the relationship between the structure of α-Syn oligomers and their toxicity. The proposed work also aims to determine the extent to which α-Syn oligomers with different structures exert toxic effects to the specific subsets of neurons.