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Science. 2017 Sep 22;357(6357):1255-1261. doi: 10.1126/science.aam9080. Epub 2017 Sep 7.

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

Author information

1
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
2
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129, USA.
3
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
4
Department for Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, DZNE, German Centre for Neurodegenerative Diseases, Tübingen, Germany.
5
Graduate School for Cellular and Molecular Neuroscience, University of Tübingen, Germany.
6
Clinical and Experimental Neuroscience, Luxembourg Center for Systems Biomedicine, University of Luxembourg, Luxembourg.
7
Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.
8
Centre Hospitalier Luxembourg, Luxembourg.
9
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. dkrainc@nm.org.

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.

PMID:
28882997
PMCID:
PMC6021018
DOI:
10.1126/science.aam9080
[Indexed for MEDLINE]
Free PMC Article

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