Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

doi:10.1073/pnas.0601891103

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

*Department of Biology, University of Pennsylvania, and
^§Howard Hughes Medical Institute, Philadelphia, PA 19104; and
^†The Stokes Research Institute, Children’s Hospital of Philadelphia, Philadelphia, PA 19104

Edited by Arthur Horwich, Yale University School of Medicine, New Haven, CT, and approved June 28, 2006 (received for review March 8, 2006)

Abstract

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.

Footnotes

^¶To whom correspondence should be addressed. E-mail: nbonini{at}sas.upenn.edu
↵ ^‡Permanent address: Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
Author contributions: M.C.M., L.T., H.I., and N.M.B. designed research; M.C.M., K.X., and L.T. performed research; M.C.M. and K.X. contributed new reagents/analytic tools; M.C.M., K.X., L.T., H.I., and N.M.B. analyzed data; and M.C.M. and N.M.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviation:

hDJ-1,

human DJ-1.
Freely available online through the PNAS open access option.