Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 37, Pages 14807-14812Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0703219104
Keywords
glutathione peroxidase; mitochondria; manganese superoxide dismutase; PARK7; Parkinson's disease
Categories
Funding
- NIA NIH HHS [R01 AG013966, AG 21617, AG13966, R01 AG021617] Funding Source: Medline
- NIEHS NIH HHS [ES013177, P30 ES013508, R21 ES013177, ES013508] Funding Source: Medline
- NINDS NIH HHS [R01 NS042269, P01 NS016375, NS42269, NS11766, P01 NS011766, P50 NS038377, NS38377, NS054817, NS16375, P50 NS038370, NS38370] Funding Source: Medline
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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 H2O2 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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