Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

TLDR

Mitochondrial and lysosomal dysfunction are implicated in substantia nigra dopaminergic neurodegeneration in Parkinson’s disease, yet the link between these pathways in human neurons is unclear. The study examined dopaminergic neurons derived from patients with idiopathic and familial Parkinson’s disease. The authors discovered that mitochondrial oxidant stress initiates dopamine oxidation, which impairs glucocerebrosidase activity, induces lysosomal dysfunction, and promotes α‑synuclein accumulation in human PD neurons—a cascade not seen in mouse neurons unless dopamine synthesis or α‑synuclein is artificially increased, thereby linking mitochondrial and lysosomal dysfunction in Parkinson’s disease pathogenesis.

Abstract

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.