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Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling.

ABSTRACT: Parkinson's disease (PD) is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. The cause of most PD cases is unknown, although postmortem studies have implicated the involvement of oxidative stress. The identification of familial PD-associated genes offers the opportunity to study mechanisms of PD pathogenesis in model organisms. Here, we show that DJ-1A, a Drosophila homologue of the familial PD-associated gene DJ-1, plays an essential role in oxidative stress response and neuronal maintenance. Inhibition of DJ-1A function through RNA interference (RNAi) results in cellular accumulation of reactive oxygen species, organismal hypersensitivity to oxidative stress, and dysfunction and degeneration of dopaminergic and photoreceptor neurons. To identify other genes that may interact with DJ-1A in regulating cell survival, we performed genetic interaction studies and identified components of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway as specific modulators of DJ-1A RNAi-induced neurodegeneration. PI3K signaling suppresses DJ-1A RNAi phenotypes at least in part by reducing cellular reactive oxygen species levels. Consistent with the genetic interaction results, we also found reduced phosphorylation of Akt in DJ-1A RNAi animals, indicating an impairment of PI3K/Akt signaling by DJ-1A down-regulation. Together with recent findings in mammalian systems, these results implicate impairments of PI3K/Akt signaling and oxidative stress response in DJ-1-associated disease pathogenesis. We also observed impairment of PI3K/Akt signaling in the fly parkin model of PD, hinting at a common molecular event in the pathogenesis of PD. Manipulation of PI3K/Akt signaling may therefore offer therapeutic benefits for the treatment of PD.

SUBMITTER: Yang Y

PROVIDER: S-EPMC1224636 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling.

Yang Yufeng Y Gehrke Stephan S Haque Md Emdadul ME Imai Yuzuru Y Kosek Jon J Yang Lichuan L Beal M Flint MF Nishimura Isao I Wakamatsu Kazumasa K Ito Shosuke S Takahashi Ryosuke R Lu Bingwei B

Proceedings of the National Academy of Sciences of the United States of America 20050909 38

Parkinson's disease (PD) is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. The cause of most PD cases is unknown, although postmortem studies have implicated the involvement of oxidative stress. The identification of familial PD-associated genes offers the opportunity to study mechanisms of PD pathogenesis in model organisms. Here, we show that DJ-1A, a Drosophila homologue of the familial PD-associated gene DJ-1, plays an essential role in oxidativ ...[more]

PMID: 16155123

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Project description:BackgroundDJ-1 is found in many tissues, including the brain, where it has been extensively studied due to its association with Parkinson's disease. DJ-1 functions as a redox-sensitive molecular chaperone and transcription regulator that robustly protects cells from oxidative stress.MethodologyRetinal pigment epithelial (RPE) cultures were treated with H2O2 for various times followed by biochemical and immunohistological analysis. Cells were transfected with adenoviruses carrying the full-length human DJ-1 cDNA and a mutant construct, which has the cysteine residues at amino acid 46, 53 and 106 mutated to serine (C to S) prior to stress experiments. DJ-1 localization, levels of expression and reactive oxygen species (ROS) generation were also analyzed in cells expressing exogenous DJ-1 under baseline and oxidative stress conditions. The presence of DJ-1 and oxidized DJ-1 was evaluated in human RPE total lysates. The distribution of DJ-1 was assessed in AMD and non-AMD cryosectionss and in isolated human Bruch's membrane (BM)/choroid from AMD eyes.Principal findingsDJ-1 in RPE cells under baseline conditions, displays a diffuse cytoplasmic and nuclear staining. After oxidative challenge, more DJ-1 was associated with mitochondria. Increasing concentrations of H2O2 resulted in a dose-dependent increase in DJ-1. Overexpression of DJ-1 but not the C to S mutant prior to exposure to oxidative stress led to significant decrease in the generation of ROS. DJ-1 and oxDJ-1 intensity of immunoreactivity was significantly higher in the RPE lysates from AMD eyes. More DJ-1 was localized to RPE cells from AMD donors with geographic atrophy and DJ-1 was also present in isolated human BM/choroid from AMD eyes.Conclusions/significanceDJ-1 regulates RPE responses to oxidative stress. Most importantly, increased DJ-1 expression prior to oxidative stress leads to decreased generation of ROS, which will be relevant for future studies of AMD since oxidative stress is a known factor affecting this disease.

Dataset Information

Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling.

Publications

Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling.

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