DJ-1 mutations are a very rare cause of recessive parkinsonism and appear to act in a parallel manner to two more common genes, PINK1 and parkin, to influence mitochondrial function. Specifically, DJ-1 is thought to play a role in oxidative stress as it is known to have a highly reactive cysteine residue. Understanding the function of DJ-1 has been hampered by the fact that there are no animal models that have clear phenotypes. To address this, we are currently crossing DJ-1 deficient animals with accelerated aging models. This will test the hypothesis, in vivo, that DJ-1 sensitizes the brain to chronic oxidative stress, which is a correlate of aging. While generating these animals we have also performed several large scale experiments to characterize the molecular events occurring in the brains of both DJ-1 deficient and accelerated aging mice. Preliminary results suggest that there are changes to both bioenergetics in both lines, suggesting that it will be interesting to examine the results of crosses between the two.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000953-12
Application #
8736666
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2013
Total Cost
$281,612
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Prahlad, Janani; Hauser, David N; Milkovic, Nicole M et al. (2014) Use of cysteine-reactive cross-linkers to probe conformational flexibility of human DJ-1 demonstrates that Glu18 mutations are dimers. J Neurochem 130:839-53
Hauser, David N; Dillman, Allissa A; Ding, Jinhui et al. (2014) Post-translational decrease in respiratory chain proteins in the Polg mutator mouse brain. PLoS One 9:e94646
Blackinton, Jeff; Kumaran, Ravindran; van der Brug, Marcel P et al. (2009) Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease. Neurosci Lett 452:8-11
Blackinton, Jeff; Lakshminarasimhan, Mahadevan; Thomas, Kelly J et al. (2009) Formation of a stabilized cysteine sulfinic acid is critical for the mitochondrial function of the parkinsonism protein DJ-1. J Biol Chem 284:6476-85