Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct

The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily alpha -synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and alpha -synuctein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to alpha -synuctein and was selective for the protofibril-to-fibril conversion, causing accumulation of the alpha -synuctein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of alpha -synuctein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.