Molecular Mechanisms of Purkinje Cell Degeneration in Ataxia-Telangiectasia
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PROVIDER: PRJNA762121 | ENA |
REPOSITORIES: ENA
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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: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: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: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:Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by loss of Purkinje cells in the cerebellum. SCA6 is caused by CAG trinucleotide repeat expansion in CACNA1A, which encodes Cav2.1, ?1A subunit of P/Q-type calcium channel. However, the pathogenic mechanism and effective therapeutic treatments are still unknown. Here we have succeeded in generation of differentiated Purkinje cells that carry the patient genes by combining disease-specific iPS cells and self-organizing culture technologies. SCA6-iPS cells derived Purkinje cells exhibited increased level of whole Cav2.1 protein while decreased level of its C-terminal fragment and downregulation of the transcriptional targets TAF1 and BTG1. We further demonstrate that SCA6-Purkinje cells exhibit thyroid hormone depletion-dependent degeneration, which can be suppressed by two compounds, thyroid releasing hormone and Riluzole. Thus we have constructed an in vitro disease model recapitulating both ontogenesis and pathogenesis. This model would be useful for pathogenic investigation and drug screening. Examination of mRNA profile in 1 ES cell line, two healthy donnor-derived iPS cell lines, three case-derived iPS cell lines and 1 normal dermal fibroblasts.
2016-11-08 | E-GEOD-85347 | biostudies-arrayexpress
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: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
Project description:Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by loss of Purkinje cells in the cerebellum. It is known to be caused by CAG trinucleotide repeat expansion in CACNA1A, the gene that encodes Cav2.1, α1A subunit of P/Q-type calcium channel. However, the pathogenic mechanism and effective therapeutic treatments are still unknown. Here we have succeeded in generation of mature Purkinje cells that carry the patient genes by combining patient-derived iPS cell and self-organizing culture technologies. Patient-derived Purkinje cells exhibited upregulation of whole Cav2.1 protein while downregulation of its C-terminal fragment and the transcriptional targets TAF1 and BTG1. We further demonstrate that patient Purkinje cells exhibit thyroid hormone depletion-dependent degeneration, which can be suppressed by two compounds, thyroid releasing hormone and Riluzole. Thus we have constructed an in vitro disease model recapitulating both ontogenesis and pathogenesis. This model would be useful for pathogenic investigation and drug screening
2016-11-08 | GSE85348 | GEO
Project description:Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by loss of Purkinje cells in the cerebellum. SCA6 is caused by CAG trinucleotide repeat expansion in CACNA1A, which encodes Cav2.1, α1A subunit of P/Q-type calcium channel. However, the pathogenic mechanism and effective therapeutic treatments are still unknown. Here we have succeeded in generation of differentiated Purkinje cells that carry the patient genes by combining disease-specific iPS cells and self-organizing culture technologies. SCA6-iPS cells derived Purkinje cells exhibited increased level of whole Cav2.1 protein while decreased level of its C-terminal fragment and downregulation of the transcriptional targets TAF1 and BTG1. We further demonstrate that SCA6-Purkinje cells exhibit thyroid hormone depletion-dependent degeneration, which can be suppressed by two compounds, thyroid releasing hormone and Riluzole. Thus we have constructed an in vitro disease model recapitulating both ontogenesis and pathogenesis. This model would be useful for pathogenic investigation and drug screening.
2016-11-08 | GSE85347 | GEO