Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mitochondrial dysfunction by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE13035 | GEO | 2008/12/01

SECONDARY ACCESSION(S): PRJNA109707

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of mouse HtrA2 knockout mice with a movement disorder (possible Parkinsons model) reveals mitochondrial dysfunction by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

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

Differentially expressed genes in brain tissue from HtrA2 knockout mice

2008-12-01 | GSE13033 | GEO

Transcription profiling of mouse brain tissue from HtrA2 knockouts

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

Differentially regulated genes in HtrA2 knockout MEFs upon rotenone treatment

2008-12-01 | GSE13034 | GEO

Transcription profiling of mouse embryonic fibroblasts from HtrA2 knockoutafter rotenone treatment. HtrA2 knockout mice have a movement disorder which may be similar to Parkinsons disease

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 Î¼M 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

Gene expression profiling of HUVECs with different HtrA2/Omi

Project description:Our previous experiments suggested that HtrA2/Omi could regulate the transcription of certain genes through its PDZ domain. Here, we used an inducible Tet-On system to mimic stress-induced HtrA2/Omi upregulation and RNA sequencing to study its influence.

2022-05-12 | GSE201703 | GEO

Gene expression profiling of HtrA2/Omi S400D mice liver

Project description:To study the role of HtrA2/Omi S400 phosphorylation, we generated knock in mice with HtrA2/Omi S400D mutation which mimics constitutive S400 phosphorylation of HtrA2/Omi.

2023-01-29 | GSE223095 | GEO

Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells

Project description:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD. A total of 9 samples were analyzed: 3 control samples, 3 samples treated with 100ug/ml of Cigarette Smoke Condensate, and 3 samples treated with 250ug/ml of Cigarettes Smoke Condensate.

2014-01-30 | E-GEOD-49107 | biostudies-arrayexpress

Regulation of the HTRA2 protease activity by PDZ domain-binding peptide ligands and the influence on HTRA2-specific protein interaction networks in retinal tissues

Project description:For the identification of HTRA2-specific protein interaction partners in retinal tissues of the house swine (Sus scrofa), we performed co-immunoprecipitation experiments with recombinant 6His-tag HTRA2 followed by quantitative LC-MS-based proteomics (see Fig. 2A and File S1). In brief, 2 µg recombinant 6His-tag HTRA2 (HTRA2 group) were spiked into 5 mg homogenized porcine retina and was subsequently enriched with the bounded protein interaction partners via Ni-NTA affinity purification (n=3). In addition, two further sample groups were treated with 10 µg UCF 101 (UCF-101 group) or 10 µg synthetic CDR peptide (CDR group) to unravel the influence of both molecules on the HTRA2-specific protein interactome in the retinal tissues (n=3 for each group). Eluate fractions of each group were separated by 1-D SDS PAGE (Fig. S1) and subsequently subjected to in-gel trypsin digestion. To distinguish unspecific from HTRA2 specific binders, we also included a control Ni-NTA bead group (CTRL group) for the quantitative MS analysis (n=3).

2021-10-11 | PXD024442 | Pride

HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence

Project description:Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation sequencing (ChIP)-quantitative PCR (qPCR), we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB–HKDC1 axis was essential for PINK1/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels (VDACs), with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and mitochondria-lysosome contact.Interestingly, the kinase regulated mitophagy and lysosomal repair independently from its function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage–induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a novel factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.

2024-01-31 | GSE226743 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data