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

Lena Friederike Burbulla, Pingping Song, Joseph Robert Mazzulli, Enrico Zampese, Yvette C. Wong, Sohee Jeon, David P. Santos, Judith Blanz, Carolin D. Obermaier, Chelsee Strojny, Jeffrey Nicholas Savas, Evangelos Kiskinis, Xiaoxi Zhuang, Rejko Krüger, Dalton James Surmeier Jr, Dimitri Krainc

Research output: Contribution to journalArticle

  • 53 Citations

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 a-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 a-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.

LanguageEnglish (US)
Pages1255-1261
Number of pages7
JournalScience
Volume357
Issue number6357
DOIs
StatePublished - Sep 22 2017

Fingerprint

Parkinson Disease
Dopamine
Synucleins
Neurons
Glucosylceramidase
Poisons
Dopaminergic Neurons
Substantia Nigra
Mesencephalon
Oxidants
Phenotype

ASJC Scopus subject areas

  • General

Cite this

Burbulla, Lena Friederike ; Song, Pingping ; Mazzulli, Joseph Robert ; Zampese, Enrico ; Wong, Yvette C. ; Jeon, Sohee ; Santos, David P. ; Blanz, Judith ; Obermaier, Carolin D. ; Strojny, Chelsee ; Savas, Jeffrey Nicholas ; Kiskinis, Evangelos ; Zhuang, Xiaoxi ; Krüger, Rejko ; Surmeier Jr, Dalton James ; Krainc, Dimitri. / Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. In: Science. 2017 ; Vol. 357, No. 6357. pp. 1255-1261.
@article{ff0a6a5d708d47bda38727e0248a3c3a,
title = "Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease",
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 a-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 a-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.",
author = "Burbulla, {Lena Friederike} and Pingping Song and Mazzulli, {Joseph Robert} and Enrico Zampese and Wong, {Yvette C.} and Sohee Jeon and Santos, {David P.} and Judith Blanz and Obermaier, {Carolin D.} and Chelsee Strojny and Savas, {Jeffrey Nicholas} and Evangelos Kiskinis and Xiaoxi Zhuang and Rejko Kr{\"u}ger and {Surmeier Jr}, {Dalton James} and Dimitri Krainc",
year = "2017",
month = "9",
day = "22",
doi = "10.1126/science.aam9080",
language = "English (US)",
volume = "357",
pages = "1255--1261",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6357",

}

Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. / Burbulla, Lena Friederike; Song, Pingping; Mazzulli, Joseph Robert; Zampese, Enrico; Wong, Yvette C.; Jeon, Sohee; Santos, David P.; Blanz, Judith; Obermaier, Carolin D.; Strojny, Chelsee; Savas, Jeffrey Nicholas; Kiskinis, Evangelos; Zhuang, Xiaoxi; Krüger, Rejko; Surmeier Jr, Dalton James; Krainc, Dimitri.

In: Science, Vol. 357, No. 6357, 22.09.2017, p. 1255-1261.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

AU - Burbulla, Lena Friederike

AU - Song, Pingping

AU - Mazzulli, Joseph Robert

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 Nicholas

AU - Kiskinis, Evangelos

AU - Zhuang, Xiaoxi

AU - Krüger, Rejko

AU - Surmeier Jr, Dalton James

AU - Krainc, Dimitri

PY - 2017/9/22

Y1 - 2017/9/22

N2 - 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 a-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 a-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.

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 a-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 a-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.

UR - http://www.scopus.com/inward/record.url?scp=85029038928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029038928&partnerID=8YFLogxK

U2 - 10.1126/science.aam9080

DO - 10.1126/science.aam9080

M3 - Article

VL - 357

SP - 1255

EP - 1261

JO - Science

T2 - Science

JF - Science

SN - 0036-8075

IS - 6357

ER -