E-GEOD-75852
Ontology highlight
ABSTRACT:
PROVIDER: E-GEOD-75852 | ExpressionAtlas | 2025-01-24
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-GEOD-75852-analysis-methods.tsv | Tabular | |||
| E-GEOD-75852-analytics.tsv | Tabular | |||
| E-GEOD-75852-atlasExperimentSummary.Rdata | Rdata | |||
| E-GEOD-75852-configuration.xml | Xml | |||
| E-GEOD-75852-g1_g3-mvaPlot.png | Other |
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Project description:Ataxia-telangiectasia cerebellar cortex expression
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Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. Human frozen tissue was obtained from the NICHD Brain and Tissue Bank of Developmental Disorders at the University of Maryland, Baltimore, MD. RNA was prepared and run on an Illumina Human HT-12 v4 microarray. 3 ataxia-telangiectasia (A-T) cases and 4 normal controls.
2015-10-30 | E-GEOD-61019 | biostudies-arrayexpress
Project description:Ataxia-telangiectasia cerebellar cortex expression
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Project description:Cerebellar differentiation in Ataxia-Telangiectasia
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Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency.
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Project description:ZNF804A transcriptome networks in differentiating human neurons derived from induced pluripotent stem cells
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Project description:Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC-derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA-mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells.
2019-05-31 | GSE114815 | GEO
Project description:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and the progressive death of cerebellar Purkinje neurons. It is unclear how the loss of sacsin function causes these deficits, or why they manifest as cerebellar ataxia. Here, we performed multi-omic profiling in sacsin knockout (KO) cells, and identified alterations in microtubule dynamics, protein trafficking, and mislocalization of synaptic and focal adhesion proteins, including multiple integrins. Focal adhesion structure, signaling, and function were affected in KO cells, which could be rescued by reducing levels of PTEN, an overabundant negative regulator of focal adhesion signaling. Purkinje neurons in ARSACS mice possessed mislocalization of ITGA1, and disorganization of synaptic structures in the deep cerebellar nucleus (DCN). Interactome analysis revealed that sacsin regulates protein-protein interactions between structural and synaptic adhesion proteins. Our findings suggest that disrupted trafficking of synaptic adhesion proteins is a causal molecular deficit underlying ARSACS.
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Project description:Background & Aims: Loss of ataxia-telangiectasia mutated, occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. This study investigated the detailed molecular mechanism through which ataxia-telangiectasia mutated expression affects the prognosis of pancreatic-cancer patients Methods: Ataxia-telangiectasia mutated and phosphorylated ataxia-telangiectasia mutated levels in pancreatic-cancer patients who underwent surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ataxia-telangiectasia mutated-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the involvement of ataxia-telangiectasia mutated in pancreatic cancer. Results: Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ataxia-telangiectasia mutated and phosphorylated ataxia-telangiectasia mutated, respectively. Low phosphorylated ataxia-telangiectasia mutated expression substantially reduced overall and disease-free survival in pancreatic-cancer patients. Loss of ataxia-telangiectasia mutated promoted MET and NTN1 over-expression via hypoxia-inducible factor-1α, thereby enhancing pancreatic-cancer cell proliferation and migration. Conclusions: These results demonstrate that the loss of ataxia-telangiectasia mutated activates downstream proto-oncogenes, inhibits apoptosis, and promotes tumor growth; moreover, loss of phosphorylated ataxia-telangiectasia mutated leads to poor prognosis in pancreatic-cancer patients. Thus, ataxia-telangiectasia mutated may serve as a potential molecular marker to monitor patient prognosis and as a potential target for pancreatic cancer therapy
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