Journal Article

DZNE-2020-05838

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.

Burbulla, L. F. ; Song, P. ; Mazzulli, J. R. ; Zampese, E. ; Wong, Y. C. ; Jeon, S. ; Santos, D. P. ; Blanz, J. ; Obermaier, C. D.DZNE* ; Strojny, C. ; Savas, J. N. ; Kiskinis, E. ; Zhuang, X. ; Krüger, R.DZNE* ; Surmeier, D. J. ; Krainc, D. (Corresponding author)

2017
Assoc.60841 Washington, DC

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Please use a persistent id in citations: doi:10.1126/science.aam9080

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.

Keyword(s): Animals (MeSH) ; Antioxidants: pharmacology (MeSH) ; Calcineurin Inhibitors: pharmacology (MeSH) ; Cell Line (MeSH) ; Disease Models, Animal (MeSH) ; Dopamine: metabolism (MeSH) ; Dopaminergic Neurons: metabolism (MeSH) ; Glucosylceramidase: deficiency (MeSH) ; Humans (MeSH) ; Lysosomes: metabolism (MeSH) ; Melanins: metabolism (MeSH) ; Mesencephalon: enzymology (MeSH) ; Mesencephalon: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: enzymology (MeSH) ; Mitochondria: metabolism (MeSH) ; Oxidation-Reduction (MeSH) ; Oxidative Stress: drug effects (MeSH) ; Parkinson Disease: enzymology (MeSH) ; Parkinson Disease: genetics (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Protein Deglycase DJ-1: genetics (MeSH) ; Substantia Nigra: enzymology (MeSH) ; Substantia Nigra: metabolism (MeSH) ; Tacrolimus: pharmacology (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; Antioxidants ; Calcineurin Inhibitors ; Melanins ; alpha-Synuclein ; neuromelanin ; PARK7 protein, human ; Protein Deglycase DJ-1 ; Glucosylceramidase ; Dopamine ; Tacrolimus

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Contributing Institute(s):

1. AG N.N. (AG N.N. 3)
2. Parkinson Genetics (AG Gasser 1)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 60 ; JCR ; SCOPUS ; Web of Science Core Collection ; Zoological Record

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