DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase

Eva Andres-Mateos, Celine Perier, Li Zhang, Beatrice Blanchard-Fillion, Todd M. Greco, Bobby Thomas, Hanseok Seok Ko, Masayuki Sasaki, Harry Ischiropoulos, Serge Przedborski, Ted M Dawson, Valina Dawson

Research output: Contribution to journalArticle

Abstract

Parkinson's disease (PD) is a common neurodegenerative movement disorder. Whereas the majority of PD cases are sporadic, rare genetic defects have been linked to this prevalent movement disorder. Mutations in DJ-1 are associated with autosomal recessive early-onset PD. The exact biochemical function of DJ-1 has remained elusive. Here we report the generation of DJ-1 knockout (KO) mice by targeted deletion of exon 2 and exon 3. There is no observable degeneration of the central dopaminergic pathways, and the mice are anatomically and behaviorally similar to WT mice. Fluorescent Amplex red measurements of H 2O2 indicate that isolated mitochondria from young and old DJ-1 KO mice have a 2-fold increase in H2O2. DJ-1 KO mice of 2-3 months of age have a 60% reduction in mitochondrial aconitase activity without compromising other mitochondrial processes. At an early age there are no differences in antioxidant enzymes, but in older mice there is an up-regulation of mitochondrial manganese superoxide dismutase and glutathione peroxidase and a 2-fold increase in mitochondrial glutathione peroxidase activity. Mutational analysis and mass spectrometry reveal that DJ-1 is an atypical peroxiredoxin-like peroxidase that scavenges H2O2 through oxidation of Cys-106. In vivo there is an increase of DJ-1 oxidized at Cys-106 after 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine intoxication of WT mice. Taken together these data indicate that the DJ-1 KO mice have a deficit in scavenging mitochondrial H2O2 due to the physiological function of DJ-1 as an atypical peroxiredoxin-like peroxidase.

Original languageEnglish (US)
Pages (from-to)14807-14812
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number37
DOIs
StatePublished - Sep 11 2007

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Peroxiredoxins
Gene Deletion
Knockout Mice
Peroxidase
Movement Disorders
Glutathione Peroxidase
Parkinson Disease
Exons
Aconitate Hydratase
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Parkinsonian Disorders
Neurodegenerative Diseases
Superoxide Dismutase
Mass Spectrometry
Mitochondria
Up-Regulation
Antioxidants
Mutation
Enzymes

Keywords

  • Glutathione peroxidase
  • Manganese superoxide dismutase
  • Mitochondria
  • PARK7
  • Parkinson's disease

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. / Andres-Mateos, Eva; Perier, Celine; Zhang, Li; Blanchard-Fillion, Beatrice; Greco, Todd M.; Thomas, Bobby; Ko, Hanseok Seok; Sasaki, Masayuki; Ischiropoulos, Harry; Przedborski, Serge; Dawson, Ted M; Dawson, Valina.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 37, 11.09.2007, p. 14807-14812.

Research output: Contribution to journalArticle

Andres-Mateos, E, Perier, C, Zhang, L, Blanchard-Fillion, B, Greco, TM, Thomas, B, Ko, HS, Sasaki, M, Ischiropoulos, H, Przedborski, S, Dawson, TM & Dawson, V 2007, 'DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 37, pp. 14807-14812. https://doi.org/10.1073/pnas.0703219104
Andres-Mateos, Eva ; Perier, Celine ; Zhang, Li ; Blanchard-Fillion, Beatrice ; Greco, Todd M. ; Thomas, Bobby ; Ko, Hanseok Seok ; Sasaki, Masayuki ; Ischiropoulos, Harry ; Przedborski, Serge ; Dawson, Ted M ; Dawson, Valina. / DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 37. pp. 14807-14812.
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AU - Andres-Mateos, Eva

AU - Perier, Celine

AU - Zhang, Li

AU - Blanchard-Fillion, Beatrice

AU - Greco, Todd M.

AU - Thomas, Bobby

AU - Ko, Hanseok Seok

AU - Sasaki, Masayuki

AU - Ischiropoulos, Harry

AU - Przedborski, Serge

AU - Dawson, Ted M

AU - Dawson, Valina

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N2 - Parkinson's disease (PD) is a common neurodegenerative movement disorder. Whereas the majority of PD cases are sporadic, rare genetic defects have been linked to this prevalent movement disorder. Mutations in DJ-1 are associated with autosomal recessive early-onset PD. The exact biochemical function of DJ-1 has remained elusive. Here we report the generation of DJ-1 knockout (KO) mice by targeted deletion of exon 2 and exon 3. There is no observable degeneration of the central dopaminergic pathways, and the mice are anatomically and behaviorally similar to WT mice. Fluorescent Amplex red measurements of H 2O2 indicate that isolated mitochondria from young and old DJ-1 KO mice have a 2-fold increase in H2O2. DJ-1 KO mice of 2-3 months of age have a 60% reduction in mitochondrial aconitase activity without compromising other mitochondrial processes. At an early age there are no differences in antioxidant enzymes, but in older mice there is an up-regulation of mitochondrial manganese superoxide dismutase and glutathione peroxidase and a 2-fold increase in mitochondrial glutathione peroxidase activity. Mutational analysis and mass spectrometry reveal that DJ-1 is an atypical peroxiredoxin-like peroxidase that scavenges H2O2 through oxidation of Cys-106. In vivo there is an increase of DJ-1 oxidized at Cys-106 after 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine intoxication of WT mice. Taken together these data indicate that the DJ-1 KO mice have a deficit in scavenging mitochondrial H2O2 due to the physiological function of DJ-1 as an atypical peroxiredoxin-like peroxidase.

AB - Parkinson's disease (PD) is a common neurodegenerative movement disorder. Whereas the majority of PD cases are sporadic, rare genetic defects have been linked to this prevalent movement disorder. Mutations in DJ-1 are associated with autosomal recessive early-onset PD. The exact biochemical function of DJ-1 has remained elusive. Here we report the generation of DJ-1 knockout (KO) mice by targeted deletion of exon 2 and exon 3. There is no observable degeneration of the central dopaminergic pathways, and the mice are anatomically and behaviorally similar to WT mice. Fluorescent Amplex red measurements of H 2O2 indicate that isolated mitochondria from young and old DJ-1 KO mice have a 2-fold increase in H2O2. DJ-1 KO mice of 2-3 months of age have a 60% reduction in mitochondrial aconitase activity without compromising other mitochondrial processes. At an early age there are no differences in antioxidant enzymes, but in older mice there is an up-regulation of mitochondrial manganese superoxide dismutase and glutathione peroxidase and a 2-fold increase in mitochondrial glutathione peroxidase activity. Mutational analysis and mass spectrometry reveal that DJ-1 is an atypical peroxiredoxin-like peroxidase that scavenges H2O2 through oxidation of Cys-106. In vivo there is an increase of DJ-1 oxidized at Cys-106 after 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine intoxication of WT mice. Taken together these data indicate that the DJ-1 KO mice have a deficit in scavenging mitochondrial H2O2 due to the physiological function of DJ-1 as an atypical peroxiredoxin-like peroxidase.

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