Formation of dopamine-mediated α-synuclein-soluble oligomers requires methionine oxidation

Abstract

α-Synuclein is the major component of the intracellular Lewy body inclusions present in Parkinson disease (PD) neurons. PD involves the loss of dopaminergic neurons in the substantia nigra and the subsequent depletion of dopamine (DA) in the striatum. DA can inhibit α-synuclein fibrillization in vitro and promote α-synuclein aggregation into soluble oligomers. We have studied the mechanism by which DA mediates α-synuclein aggregation into soluble oligomers. Reacting α-synuclein with DA increased the mass of α-synuclein by 64 Da. NMR showed that all four methionine residues were oxidized by DA, consistent with the addition of 64 Da. Substituting all four methionines to alanine significantly r..