Cellular senescence drives inflammation and neurodegeneration in Ataxia-Telangiectasia brain organoids
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ABSTRACT:
PROVIDER: PRJEB43363 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR5385150_1.fastq.gz | Fastqsanger.gz | |||
| ERR5385150_2.fastq.gz | Fastqsanger.gz | |||
| ERR5385151_1.fastq.gz | Fastqsanger.gz | |||
| ERR5385151_2.fastq.gz | Fastqsanger.gz | |||
| ERR5385152_1.fastq.gz | Fastqsanger.gz |
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Project description:The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased histone H3K27 trimethylation (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) also plays an important role in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is identified as a new ATM kinase target, and its S734 phosphorylation reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3in ATM deficiency. ChIP-sequencing shows a significant increase in H3K27me3 ‘marks’ and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle re-entry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescues Purkinje cell degeneration and behavioral abnormalities in Atm / mice, demonstrating that EZH2-mediated H3K27me3 is another key factor in A-T neurodegeneration. Two samples each were run of brain total RNA from Atm+/+ and Atm-/- mice.
2013-10-25 | E-GEOD-50951 | biostudies-arrayexpress
Project description:The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased histone H3K27 trimethylation (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) also plays an important role in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is identified as a new ATM kinase target, and its S734 phosphorylation reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3in ATM deficiency. ChIP-sequencing shows a significant increase in H3K27me3 ‘marks’ and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle re-entry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescues Purkinje cell degeneration and behavioral abnormalities in Atm / mice, demonstrating that EZH2-mediated H3K27me3 is another key factor in A-T neurodegeneration.
2013-10-25 | GSE50951 | GEO
Project description:MicroRNA dysregulation in Ataxia Telangiectasia
| PRJNA1107187 | ENA
Project description:Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
2017-12-20 | GSE76380 | GEO
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 mutated (ATM) is a protein that belongs to the family of phosphatidylinositol 3-kinase (PI3K)-like serine/threonine kinases. Initially identified as a nuclear protein essential for the DNA damage response (DDR) in mitotic cells, it serves as repair coordinator for DNA double-strand breaks (DSBs). Dysfunction of the ATM protein underlies ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by immunodeficiency and progressive cerebellar degeneration leading to ataxia. The cause of cerebellar neurodegeneration cannot be explained at present, given that in postmitotic neurons ATM has a cytoplasmic localization. The non-nuclear functions of ATM and their mechanistic link to cerebellar degeneration in A-T remain elusive. In this study we established both phosphoproteomic and proteomic profiles of ATM deficiency in neuroblastoma cells and mouse cerebellum tissue to identify the underlying molecular mechanism and relevant signaling networks.
2025-09-29 | PXD058394 | Pride
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.
2015-10-30 | GSE61019 | GEO
Project description:Disease-specific induced pluripotent stem (iPS) cells have been used for a model to analyze pathogenesis of the disease. In this study, we generated iPS cells derived from a fibroblastic cell line of ataxia telangiectasia (AT-iPS cells), a neurodegenerative, inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. AT-iPS cells exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. Surprisingly, while parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro, i.e. maintenance of intact chromosomes at least by 80 passages (560 days) probably due to robust stability of pluripotent stem cells such as iPS cells and embryonic stem cells. The whole exome analysis also showed comparable nucleotide substitution speed in AT-iPS cells. Interestingly, after longer period of AT-iPS implantation into immunodeficient mice, teratoma generated by AT-iPS cells exhibited telangiectasia and carcinogenesis that are two characteristic symptoms of ataxia telangiectasia. Taken together, AT-iPS cells would be a good model for ataxia telangiectasia to clarify pathogenesis of the disease, and may allow us to facilitate development of drugs that inhibit ataxia and hypersensitivity to ionizing radiation for therapeutic application.
2013-06-22 | GSE47498 | GEO
Project description:Ataxia Telangiectasia (AT) is a rare disorder characterized by neurodegeneration, combined immunodeficiency, predisposition to malignancies and high clinical variability. MicroRNAs (miRNAs) profiling may provide information on the pathophysiology of complex rare human diseases as they are involved in numerous biological functions including proliferation, differentiation, and DNA repair. To investigate the differential expression of miRNAs in AT patient samples with the aim of identifying miRNA signatures and correlate these patterns with disease pathogenesis. Twenty AT patients (mean age 17.7 + 9.6 years) were enrolled in the study. Clinical and genetic data were collected. We performed a small RNA-seq analysis in PBMCs and fibroblasts to compare miRNA expression profiles in AT patients and controls, and to identify specific expression signatures for AT. We found 42 differentially expressed (DE)-miRNAs in blood samples and 26 in fibroblasts samples. Three DE-miRNAs, miR-342-3p, miR-30a-5p, and miR-195-5p were validated in further AT samples and their dysregulation was confirmed.We identified for the first time, an AT-associated miRNA signature in blood cells and fibroblast samples obtained from a cohort of AT patients. Several pathways were predicted commonly deregulated, mainly involved in cancer. miRNAs may provide information on AT pathophysiology and tumorigenesis.
2024-10-01 | GSE266440 | GEO
Project description:Disease-specific induced pluripotent stem (iPS) cells have been used for a model to analyze pathogenesis of the disease. In this study, we generated iPS cells derived from a fibroblastic cell line of ataxia telangiectasia (AT-iPS cells), a neurodegenerative, inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. AT-iPS cells exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. Surprisingly, while parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro, i.e. maintenance of intact chromosomes at least by 80 passages (560 days) probably due to robust stability of pluripotent stem cells such as iPS cells and embryonic stem cells. The whole exome analysis also showed comparable nucleotide substitution speed in AT-iPS cells. Interestingly, after longer period of AT-iPS implantation into immunodeficient mice, teratoma generated by AT-iPS cells exhibited telangiectasia and carcinogenesis that are two characteristic symptoms of ataxia telangiectasia. Taken together, AT-iPS cells would be a good model for ataxia telangiectasia to clarify pathogenesis of the disease, and may allow us to facilitate development of drugs that inhibit ataxia and hypersensitivity to ionizing radiation for therapeutic application. The parental AT1OS fibroblast cells and four independent AT-iPS clones were subjected to Illumina HumanCytoSNP-12 v2.1 BeadChip analysis.
2013-06-22 | E-GEOD-47498 | biostudies-arrayexpress