Transcriptomics,Genomics

Dataset Information

32

RNA binding activity of the recessive parkinsonism protein DJ-1


ABSTRACT: Parkinson disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanism(s) involved in the degeneration of specific neuronal groups remains unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unclear, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here we show that DJ-1 associates with specific RNA targets in cells and in the brain including mitochondrial genes, genes involved in glutathione metabolism and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations in vitro and that there is some RNA sequence specificity to the association. Oxidative stress causes DJ-1 to dissociate from RNA. Using in vitro and in vivo models of mild oxidative stress, we show that DJ-1 normally suppresses translation in normal circumstances but allows translation after oxidative stress. We tested the hypothesis that these specific RNA targets are responsible for sensitivity to stress by exposing knockout flies to glutathione synthesis inhibitors and saw the predicted increased sensitivity in vivo. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds and regulates specific groups of RNA targets in an oxidationdependent manner. Furthermore, these results suggest how a small protein might both be an upstream regulator of processes important in parkinsonism and be a modifier of cancer-related processes. Keywords: Immunoprecipitated RNA comparisons Overall design: 6-8 biological replicates of RNA immunoprecipitated with DJ-1 protein was compared to RNA isolated with a nonspecific IgG control antibody in human cells, or to nonspecific RNA isolated with the DJ-1 antibody from KO mouse brains.

INSTRUMENT(S): Sentrix Human-6 Expression BeadChip

SUBMITTER: J Raphael Gibbs  

PROVIDER: GSE8632 | GEO | 2008-03-14

SECONDARY ACCESSION(S): PRJNA101815

REPOSITORIES: GEO

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Publications

RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways.

van der Brug Marcel P MP   Blackinton Jeff J   Chandran Jayanth J   Hao Ling-Yang LY   Lal Ashish A   Mazan-Mamczarz Krystyna K   Martindale Jennifer J   Xie Chengsong C   Ahmad Rili R   Thomas Kelly J KJ   Beilina Alexandra A   Gibbs J Raphael JR   Ding Jinhui J   Myers Amanda J AJ   Zhan Ming M   Cai Huaibin H   Bonini Nancy M NM   Gorospe Myriam M   Cookson Mark R MR  

Proceedings of the National Academy of Sciences of the United States of America 20080714 29


Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, alth  ...[more]

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