Research Article

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

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Science  07 Sep 2017:
DOI: 10.1126/science.aam9080

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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, ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction and α-synuclein accumulation. This toxic cascade was observed only in human, but not in mouse PD neurons, at least in part due to species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein levels 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.

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