α-synuclein membrane interactions and lipid specificity

With the discovery of missense mutations (A53T and A30P) in alpha -synuclein (alpha -Syn) in several families with early onset familial Parkinson's disease, alpha -Syn aggregation and fibril formation have been thought to play a role in the pathogenesis of alpha -synucleinopathies, such as Parkinson's disease, dementia. with Lewy bodies, and multiple system atrophy. As previous reports have suggested that alpha -Syn plays a role in lipid transport and synaptic membrane biogenesis, we investigated whether alpha -Syn binds to a specific lipid ligand using thin layer chromatography overlay and examined the changes in its secondary structure using circular dichroism spectroscopy. alpha -Syn was found to bind to acidic phospholipid vesicles and this:binding was significantly augmented by the. presence of phosphatidylethanolamine, a neutral phospholipid. We further examined the interaction of alpha -Syn with lipids by in situ atomic force microscopy. The association of soluble wild-type alpha -Syn with planar lipid bilayers resulted in extensive bilayer disruption and the formation of amorphous aggregates and small fibrils. The A53T mutant alpha -Syn disrupted the Lipid bilayers in a similar fashion but at a slower rate. These results suggest that alpha -Syn membrane interactions are physiologically important and the lipid composition of the cellular membranes may affect these interactions in vivo.