Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging.
Inherited mutations in PARK7, the gene encoding DJ-1, are associated with loss of protein function and early-onset parkinsonism. Like human DJ-1 (hDJ-1), Drosophila DJ-1b protects against oxidative insult and is modified with oxidation. We demonstrate that hDJ-1 rescues flies mutant for DJ-1b, and that a conserved cysteine residue in the fly protein (C104, analogous to C106 in hDJ-1) is critical for biological antioxidant function in vivo. Targeted mutagenesis suggests that modification of DJ-1b at this residue inactivates the protective activity of the protein against oxidative stress. Further studies show that DJ-1 modification increases dramatically with age in flies, mice, and humans, with aged flies showing strikingly increased susceptibility to oxidative stress and markedly enhanced DJ-1b modification upon oxidative challenge. Overoxidation of DJ-1 with age and exposure to oxidative toxins may lead to inactivation of DJ-1 function, suggesting a role in susceptibility to sporadic Parkinson's disease.
Meulener
Marc C
MC
Department of Biology, University of Pennsylvania, and Howard Hughes Medical Institute, Philadelphia, PA 19104, USA.
Xu
Kexiang
K
Thomson
Leonor
L
Thompson
Leonor
L
Ischiropoulos
Harry
H
Bonini
Nancy M
NM
D000375:Aging / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D003545:Cysteine / Q000378:metabolism; D004252:DNA Mutational Analysis; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D000071617:Protein Deglycase DJ-1
D029721:Drosophila Proteins; D006540:Herbicides; D009419:Nerve Tissue Proteins; C506879:DJ-1beta protein, Drosophila; D000071617:Protein Deglycase DJ-1; D003545:Cysteine; D010269:Paraquat