TY  - JOUR
AU  - Burbulla, Lena F
AU  - Song, Pingping
AU  - Mazzulli, Joseph R
AU  - Zampese, Enrico
AU  - Wong, Yvette C
AU  - Jeon, Sohee
AU  - Santos, David P
AU  - Blanz, Judith
AU  - Obermaier, Carolin D
AU  - Strojny, Chelsee
AU  - Savas, Jeffrey N
AU  - Kiskinis, Evangelos
AU  - Zhuang, Xiaoxi
AU  - Krüger, Rejko
AU  - Surmeier, D James
AU  - Krainc, Dimitri
TI  - Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.
JO  - Science / Science now
VL  - 357
IS  - 6357
SN  - 0036-8075
CY  - Washington, DC
PB  - Assoc.60841
M1  - DZNE-2020-05838
SP  - 1255-1261
PY  - 2017
AB  - 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.
KW  - Animals
KW  - Antioxidants: pharmacology
KW  - Calcineurin Inhibitors: pharmacology
KW  - Cell Line
KW  - Disease Models, Animal
KW  - Dopamine: metabolism
KW  - Dopaminergic Neurons: metabolism
KW  - Glucosylceramidase: deficiency
KW  - Humans
KW  - Lysosomes: metabolism
KW  - Melanins: metabolism
KW  - Mesencephalon: enzymology
KW  - Mesencephalon: metabolism
KW  - Mice
KW  - Mice, Knockout
KW  - Mitochondria: drug effects
KW  - Mitochondria: enzymology
KW  - Mitochondria: metabolism
KW  - Oxidation-Reduction
KW  - Oxidative Stress: drug effects
KW  - Parkinson Disease: enzymology
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: metabolism
KW  - Protein Deglycase DJ-1: genetics
KW  - Substantia Nigra: enzymology
KW  - Substantia Nigra: metabolism
KW  - Tacrolimus: pharmacology
KW  - alpha-Synuclein: metabolism
KW  - Antioxidants (NLM Chemicals)
KW  - Calcineurin Inhibitors (NLM Chemicals)
KW  - Melanins (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - neuromelanin (NLM Chemicals)
KW  - PARK7 protein, human (NLM Chemicals)
KW  - Protein Deglycase DJ-1 (NLM Chemicals)
KW  - Glucosylceramidase (NLM Chemicals)
KW  - Dopamine (NLM Chemicals)
KW  - Tacrolimus (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28882997
C2  - pmc:PMC6021018
DO  - DOI:10.1126/science.aam9080
UR  - https://pub.dzne.de/record/139516
ER  -