TY - JOUR
T1 - DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase
AU - Andres-Mateos, Eva
AU - Perier, Celine
AU - Zhang, Li
AU - Blanchard-Fillion, Beatrice
AU - Greco, Todd M.
AU - Thomas, Bobby
AU - Han, Seok Ko
AU - Sasaki, Masayuki
AU - Ischiropoulos, Harry
AU - Przedborski, Serge
AU - Dawson, Ted M.
AU - Dawson, Valina L.
PY - 2007/9/11
Y1 - 2007/9/11
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.
KW - Glutathione peroxidase
KW - Manganese superoxide dismutase
KW - Mitochondria
KW - PARK7
KW - Parkinson's disease
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U2 - 10.1073/pnas.0703219104
DO - 10.1073/pnas.0703219104
M3 - Article
C2 - 17766438
AN - SCOPUS:35548972027
SN - 0027-8424
VL - 104
SP - 14807
EP - 14812
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -