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

LF Burbulla, P Song, JR Mazzulli, E Zampese… - Science, 2017 - science.org
LF Burbulla, P Song, JR Mazzulli, E Zampese, YC Wong, S Jeon, DP Santos, J Blanz…
Science, 2017science.org
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 …
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.
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