The interplay between lipids and dopamine on α-synuclein oligomerization and membrane binding

The deposition of alpha-syn (alpha-synuclein) as amyloid fibrils and the selective loss of DA (dopamine) containing neurons in the substantia nigra are two key features of PD (Parkinson's disease). alpha-syn is a natively unfolded protein and adopts an alpha-helical conformation upon binding to lipid membrane. Oligomeric species of alpha-syn have been proposed to be the pathogenic species associated with PD because they can bind lipid membranes and disrupt membrane integrity. DA is readily oxidized to generate reactive intermediates and ROS (reactive oxygen species) and in the presence of DA, alpha-syn form of SDS-resistant soluble oligomers. It is postulated that the formation of the alpha-syn: DA oligomers involves the cross-linking of DA-melanin with alpha-syn, via covalent linkage, hydrogen and hydrophobic interactions. We investigate the effect of lipids on DA-induced alpha-syn oligomerization and studied the ability of alpha-syn: DA oligomers to interact with lipids vesicles. Our results show that the interaction of alpha-syn with lipids inhibits the formation of DA-induced alpha-syn oligomers. Moreover, the alpha-syn: DA oligomer cannot interact with lipid vesicles or cause membrane permeability. Thus, the formation of alpha-syn: DA oligomers may alter the actions of alpha-syn which require membrane association, leading to disruption of its normal cellular function.