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ABSTRACT:
PROVIDER: PRJNA109707 | ENA |
REPOSITORIES: ENA
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Project description:Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson’s disease patients’ brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases. This SuperSeries is composed of the following subset Series:; GSE13033: Differentially expressed genes in brain tissue from HtrA2 knockout mice; GSE13034: Differentially regulated genes in HtrA2 knockout MEFs upon rotenone treatment Experiment Overall Design: Refer to individual Series
2008-12-05 | E-GEOD-13035 | biostudies-arrayexpress
Project description:Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinsonâs disease patientsâ brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases. Experiment Overall Design: This experiment was set out to identify genes that are differentially expressed in brain tissue from the cortex of HtrA2 knockout (KO) mice compared to wild type (WT) littermates. We chose a cortical region since there is no evidence of neuronal loss in this region enabling us to compare mRNA transcripts in identical cellular populations. Brains of littermate WT and HtrA2 KO mice were dissected to obtain cortex tissue at post-natal day 29 (P29). RNA was isolated and samples were processed for hybridisation (6 samples in total, 3 replicates for each genotype).
2009-01-13 | E-GEOD-13033 | biostudies-arrayexpress
Project description:Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinsonâs disease patientsâ brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases. Experiment Overall Design: This experiment was set out to identify genes that are differentially regulated upon rotenone treatment in HtrA2 knockout (KO) mouse embryonic fibroblasts (MEFs) compared to wild type (WT) MEFs. Primary MEFs were isolated and at passage 4 subjected to treatment with vehicle (control) or 1 μM rotenone (rot) for 4 hrs. 3 replicates were performed. RNA was isolated and samples were processed for hybridisation (12 samples in total).
2009-01-13 | E-GEOD-13034 | biostudies-arrayexpress
Project description:Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson’s disease patients’ brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases. Keywords: genotype comparison
2008-12-01 | GSE13033 | GEO
Project description:Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson’s disease patients’ brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases. Keywords: stress response to rotenone treatment
2008-12-01 | GSE13034 | GEO
Project description:Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here we demonstrate that loss of HtrA2 results in transcriptional up-regulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson’s disease patients’ brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases. This SuperSeries is composed of the SubSeries listed below.
2008-12-01 | GSE13035 | GEO
Project description:The Alzheimer's Disease and Parkinson's Disease risk locus Fyn kinase is implicated in protein pathophysiology and NF-κB microglia inflammatory signaling. To investigate in vivo mechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging we demonstrate neural FynY531F expression leads to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Gene expression analyses reveal reduction in neuroprotective genes, and elevated inflammatory cytokines Il-1β, IL-12 and TNF-α and genes associated with oxidative stress. These phenotypes correlate with microglia activation in the larval brain. Chemical inhibition demonstrates dopaminergic neuron loss is dependent on Fyn and NF-κB/Caspase 1 signaling. We identify Stat3 activation as a novel downstream effector of Fyn signaling that acts synergistically with NF-κB in dopaminergic neuron degeneration. These results show Fyn drives neurodegeneration through NF-κB inflammatory signaling and Stat3 pathways. Activation of Stat3 provides a potential link from Fyn to mitochondrial dysfunction associated with dopaminergic neuron loss.
2024-11-25 | GSE271955 | GEO
Project description:Mitochondrial functions are largely performed by proteins imported from cytosol. Impaired protein import in mitochondria affects the maintenance of intra-mitochondrial anabolic and energy metabolic pathways. It leads to cytosolic accumulation of mistargeted proteins and activation of cellular stress responses. To explore the communication between these mechanism in mammalian system, we targeted the co-chaperone of mitochondrial Hsp70, a GrpE Like protein 1 (Grpel1), in mice. We show that loss of protein import into mitochondrial matrix results in mitochondrial dysfunction, which triggers stress responses. The total shut down of mtHSP70 function by overall knockout of Grpel1 resulted in early embryonic lethality, and tamoxifen-induced skeletal muscle-specific knockout of Grpel1 caused rapid muscular atrophy. We show here, with transcriptomics analysis, that protein-import failure in mitochondria increased cellular proteotoxic stress due to mitochondrial dysfunction. As a control mechanism, it triggered adaptive stress responses, including unfolded protein responses and integrated stress responses. Metabolic profiling of skeletal muscle-specific knockout mice revealed amino acid and TCA cycle intermediates shuttle between serum and muscle.
2022-10-04 | GSE198540 | GEO
Project description:In Parkinsonâ??s disease (PD), the progressive loss of substantia nigra dopamine cells has been associated with their vulnerability to oxidative stress, inflammation, and mitochondrial dysfunction. To identify multiple gene transcription alterations that may potentially underlie early stages of related degenerative processes in brain, we used the subcrhonic MPTP mouse model of PD and microarray analysis at 4 days post-MPTP when neurotoxic activity is maximal. Since PD results in gene changes throughout the brain, we assessed MPTP's effects in multiple regions: frontal cortex, striatum and midbrain. Experiment Overall Design: Mus musculus adults were randomly assigned to either MPTP or saline treatment groups. Brain regions of interest (frontal cortex, striatum and midbrain) were dissected from both groups for RNA extraction and hybridization on Affymetrix microarrays.
2008-10-26 | E-GEOD-7707 | biostudies-arrayexpress
Project description:Maintenance of mitochondrial homeostasis is essential for a broad spectrum of signalling, metabolic and energetic processes. Consequently, mitochondrial dysfunction is linked to the development of a wide range of myopathies and many common diseases including type 2 diabetes, Parkinson’s and Alzheimer’s diseases. In response to disturbed mitochondrial proteostasis, an organelle-specific stress response is initiated, which results in a global adaptive transcriptional response partially sharing the signature of the integrated stress response (ISR). However, the exact sequence of events of the signalling cascade resulting in the activation of the ISR remains elusive. CHOP was the first transcription factor (TF) proposed to play a role in this process, although - due to the lack of a trans-activating domain - it needs to heterodimerize with other TFs to activate or suppresses its target genes. Therefore, we decided to investigate the molecular aspects and in vivo functions of CHOP in a murine model of mitochondrial dysfunction triggered by the loss of mitochondrial translation. Disruption of mitochondrial translation by heart and skeletal muscle-specific knock-out of the mitochondrial aspartyl-tRNA synthetase DARS2 on its own results in death of the animals within 7-8 weeks. Additional deletion of CHOP even further reduces the lifespan to less than 3 weeks, suggesting an existential role of the TF within the initiated stress signalling pathway. Our recent data indicates that CHOP's impact arises from the regulation of another TF with detrimental effects when exceedingly activated under certain circumstances: ATF4.
2022-04-04 | GSE149010 | GEO