DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase.
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(2)O(2) indicate that isolated mitochondria from young and old DJ-1 KO mice have a 2-fold increase in H(2)O(2). 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 H(2)O(2) 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 H(2)O(2) due to the physiological function of DJ-1 as an atypical peroxiredoxin-like peroxidase.
Andres-Mateos
Eva
E
Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD 21205, USA.
Perier
Celine
C
Zhang
Li
L
Blanchard-Fillion
Beatrice
B
Greco
Todd M
TM
Thomas
Bobby
B
Ko
Han Seok
HS
Sasaki
Masayuki
M
Ischiropoulos
Harry
H
Przedborski
Serge
S
Dawson
Ted M
TM
Dawson
Valina L
VL
D000375:Aging / Q000502:physiology; D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D017353:Gene Deletion; D005979:Glutathione Peroxidase / Q000032:analysis / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology; D015513:Oncogene Proteins / Q000235:genetics*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D009195:Peroxidase / Q000235:genetics*; D010544:Peroxidases / Q000235:genetics*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D013482:Superoxide Dismutase / Q000032:analysis / Q000378:metabolism
D015513:Oncogene Proteins; D006861:Hydrogen Peroxide; D010544:Peroxidases; D054464:Peroxiredoxins; D009195:Peroxidase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D003545:Cysteine