Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct

TLDR

The substantia nigra in Parkinson's disease is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily α‑synuclein. We screened a library of drug‑like molecules to probe the relationship between neurodegeneration and α‑synuclein fibrilization. The study screened a library of drug‑like molecules to probe the relationship between neurodegeneration and α‑synuclein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to dopamine, and dopamine’s inhibitory activity depended on oxidative ligation to α‑synuclein, selectively blocking protofibril‑to‑fibril conversion and causing protofibril accumulation, thereby explaining dopaminergic selectivity of α‑synuclein neurotoxicity and informing PD therapeutic and diagnostic strategies.

Abstract

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