RNA binding activity of the recessive parkinsonism protein DJ-1
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE8632phs000249.v1.p1
PROVIDER: PRJNA101815 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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
2008-03-14 | GSE8632 | GEO
Project description:Mutations in the DJ-1 gene cause rare forms of autosomal recessive Parkinson's disease in humans. Recently, DJ-1 knockout rats have been generated and they have been reported to have subtle motor defects and neurodegeneration. We hypothesized that measuring the differences in mRNA expression in the brains of wildtype and DJ-1 knockout rats would provide insight into the mechanisms underlying these phenotypes. Using RNA-Seq, we were able to measure differential expression of over 2,000 genes in the DJ-1 knockout rat brains.
2017-09-11 | GSE71968 | GEO
Project description:Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4+ regulatory T cells (Treg cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs Treg survival starting in young mice and reduces Treg homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible Treg cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As Treg homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.
2022-04-19 | GSE115269 | GEO
Project description:Mutations in the DJ-1 (Park7) gene cause autosomal recessive Parkinson's disease in humans, but the function of the DJ-1 protein is poorly characterized. In an effort to understand more about the biology of DJ-1, we performed iTRAQ analyses on subcellular fractions enriched from DJ-1 knockout rat and mouse brains. We generated iTRAQ datasets for mitochondria and cytosol enriched fractions from 6-month-old rat brains, and the cytosol enriched fraction from 14-15-month old mouse brains. Our subsequent analyses of these datasets led to our discovery that the Hexokinase 1 protein was increased in the cytosol components of both DJ-1 knockout species.
2017-10-04 | PXD005215 | Pride
Project description:YajL is the most closely related Escherichia coli homolog of Parkinsonism-associated protein DJ-1, a protein with a yet undefined function in the oxidative stress response. YajL protects cells against oxidative stress-induced protein aggregation and functions as a covalent chaperone for the thiol proteome, including FeS proteins. To clarify the cellular responses to YajL deficiency, transcriptional profiling of the yajL mutant was performed. As compared to the parental strain, the yajL mutant overexpressed genes coding for chaperones, proteases, chemical chaperone transporters, superoxide dismutases, catalases, peroxidases, components of thioredoxin and glutaredoxin systems, iron transporters, ferritins and FeS cluster biogenesis enzymes, DNA-repair proteins, RNA chaperones and small regulatory RNAs. It also overexpressed the RNA polymerase stress sigma factors sigma S (multiple stresses) and sigma 32 (protein stress) and activated the OxyR and SoxRS oxidative stress transcriptional regulators, which together trigger the global stress response. The yajL mutant also overexpressed genes involved in septation and adopted a shorter and rounder shape characteristic of stressed bacteria. Biochemical experiments showed that this upregulation of many stress genes resulted in increased expression of stress proteins and improved biochemical function. Thus, protein defects resulting from the yajL mutation trigger the onset of a robust and global stress response in a prokaryotic model of DJ-1-associated Parkinsonism. We performed microarray analysis of the transcriptome response of the yajL mutant and its parental strain in the exponential phase of growth (grown in aerobiosis in LB medium to OD600 = 0.3) in the absence of any exogenous stress. Two replicates per strain (wild type, yajL mutant).
2012-12-04 | E-GEOD-42702 | biostudies-arrayexpress
Project description:YajL is the most closely related Escherichia coli homolog of Parkinsonism-associated protein DJ-1, a protein with a yet undefined function in the oxidative stress response. YajL protects cells against oxidative stress-induced protein aggregation and functions as a covalent chaperone for the thiol proteome, including FeS proteins. To clarify the cellular responses to YajL deficiency, transcriptional profiling of the yajL mutant was performed. As compared to the parental strain, the yajL mutant overexpressed genes coding for chaperones, proteases, chemical chaperone transporters, superoxide dismutases, catalases, peroxidases, components of thioredoxin and glutaredoxin systems, iron transporters, ferritins and FeS cluster biogenesis enzymes, DNA-repair proteins, RNA chaperones and small regulatory RNAs. It also overexpressed the RNA polymerase stress sigma factors sigma S (multiple stresses) and sigma 32 (protein stress) and activated the OxyR and SoxRS oxidative stress transcriptional regulators, which together trigger the global stress response. The yajL mutant also overexpressed genes involved in septation and adopted a shorter and rounder shape characteristic of stressed bacteria. Biochemical experiments showed that this upregulation of many stress genes resulted in increased expression of stress proteins and improved biochemical function. Thus, protein defects resulting from the yajL mutation trigger the onset of a robust and global stress response in a prokaryotic model of DJ-1-associated Parkinsonism.
2012-12-04 | GSE42702 | GEO
Project description: Not available
| S-EPMC2481328 | biostudies-literature
Project description:DJ-1 is a causative gene for a familial form of Parkinson disease. DJ-1 deficient mice develop progressive behavioral abnormalities in gaits and forearm grip strength are hypoactive. The mechanisms under the activity are not fully known. Here we show that DJ-1 is critical for disuse- induced skeletal muscle atrophy. Firstly, DJ-1 expression is positively correlated with muscle mass in human, and is decreased in atrophy muscle of immobilization mice and aged human. Secondly, DJ-1-deficient muscles are dystrophic, as well as impaired in activities and oxidative capacity. In disuse-atrophic condition, skeletal muscle specific-DJ-1 knockout mice show less cross section area (CSA) and more central nuclei than control mice. Thirdly, biochemical analysis indicates that these changes are due to enhanced activation of FoxO1, and subsequent upregulation of atrogenes. Finally, the inhibitor of DJ-1, compound 23, can mimic the effects of DJ-1 ablation in vivo. Our results illuminate that skeletal muscle DJ-1 has an unexpected role in the regulation of catabolic signals from mechanical stimulation, providing a therapeutic target for muscle-wasting diseases.
2023-12-12 | GSE216408 | GEO
Project description:DJ-1 is an atypical peroxiredoxin-like peroxidase that may act as a redox-dependent chaperone and a regulator of transcription. To explore DJ-1-mediated transcriptional control in Parkinsonâ??s disease (PD), we generated human neuroblastoma cells with inducible knock-down of DJ-1 expression. We then used functional genomic techniques to identify novel pathways dysregulated by loss of DJ-1 function. Using microarray gene expression profiling, we found that DJ-1 silencing alters the expression of 26 genes, with 10 down-regulated and 16 up-regulated transcripts. Among the down-regulated genes we found Ret, tyrosine kinase receptor for the neurotrophic factor GDNF. Taking advantage of Ingenuity Pathways Analysis, we identified hypoxia inducible factor 1 alpha (Hif1a) as a possible mediator of the interplay between DJ-1 and Ret. We show that Hif1a is stabilized in the absence of DJ-1, and that loss of DJ-1 generates hypoxia and accumulation of free radical species (ROS). Overexpression of wt DJ-1, but not of C106A and L166P mutants deficient in ROS scavenger activity, rescues Ret expression in neuroblastoma cells. These findings reveal novel players in PD pathogenesis and provide evidence for additional pathways involved in DJ-1-mediated neurodegeneration. Comparison between DJ-1-silenced human SH-SY5Y neuroblastoma cells and control cells. Two clones were selected for each condition, and each clone was analyzed in duplicate, for a total of 8 samples.
2010-04-28 | E-GEOD-17204 | biostudies-arrayexpress
Project description:DJ-1 is an atypical peroxiredoxin-like peroxidase that may act as a redox-dependent chaperone and a regulator of transcription. To explore DJ-1-mediated transcriptional control in Parkinson’s disease (PD), we generated human neuroblastoma cells with inducible knock-down of DJ-1 expression. We then used functional genomic techniques to identify novel pathways dysregulated by loss of DJ-1 function. Using microarray gene expression profiling, we found that DJ-1 silencing alters the expression of 26 genes, with 10 down-regulated and 16 up-regulated transcripts. Among the down-regulated genes we found Ret, tyrosine kinase receptor for the neurotrophic factor GDNF. Taking advantage of Ingenuity Pathways Analysis, we identified hypoxia inducible factor 1 alpha (Hif1a) as a possible mediator of the interplay between DJ-1 and Ret. We show that Hif1a is stabilized in the absence of DJ-1, and that loss of DJ-1 generates hypoxia and accumulation of free radical species (ROS). Overexpression of wt DJ-1, but not of C106A and L166P mutants deficient in ROS scavenger activity, rescues Ret expression in neuroblastoma cells. These findings reveal novel players in PD pathogenesis and provide evidence for additional pathways involved in DJ-1-mediated neurodegeneration.
2010-04-16 | GSE17204 | GEO