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An induced pluripotent stem cell model for ataxia telangiectasia

ABSTRACT: The difficulty associated with generating induced pluripotent stem cells (iPSC) from patients with chromosomal instability syndromes suggests the cellular DNA damage response poses a barrier to reprogramming. Here we demonstrate that fibroblasts from patients with ataxia-telangiectasia (A-T) can be reprogrammed to bona-fide iPSC, albeit at a reduced efficiency. A-T iPSC display defective radiation-induced signaling, radiosensitivity and cell cycle checkpoint defects. Bioinformatic analysis of gene expression in the A-T iPSC identifies abnormalities in DNA damage signaling pathways as well as changes in mitochondrial and pentose phosphate pathways. A-T iPSC can be differentiated into functional neurons and thus represent a suitable model system to investigate A-T associated neurodegeneration. Collectively our data show that iPSC can be generated from a chromosomal instability syndrome and that these cells can be used to discover early developmental consequences of ATM deficiency, such as altered mitochondrial function, that may be relevant to A-T pathogenesis and amenable to therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35347 | GEO | 2012/05/28

SECONDARY ACCESSION(S): PRJNA152721

REPOSITORIES: GEO

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An induced pluripotent stem cell model for ataxia telangiectasia

Project description:The difficulty associated with generating induced pluripotent stem cells (iPSC) from patients with chromosomal instability syndromes suggests the cellular DNA damage response poses a barrier to reprogramming. Here we demonstrate that fibroblasts from patients with ataxia-telangiectasia (A-T) can be reprogrammed to bona-fide iPSC, albeit at a reduced efficiency. A-T iPSC display defective radiation-induced signaling, radiosensitivity and cell cycle checkpoint defects. Bioinformatic analysis of gene expression in the A-T iPSC identifies abnormalities in DNA damage signaling pathways as well as changes in mitochondrial and pentose phosphate pathways. A-T iPSC can be differentiated into functional neurons and thus represent a suitable model system to investigate A-T associated neurodegeneration. Collectively our data show that iPSC can be generated from a chromosomal instability syndrome and that these cells can be used to discover early developmental consequences of ATM deficiency, such as altered mitochondrial function, that may be relevant to A-T pathogenesis and amenable to therapeutic intervention. Three different cell types: fibroblasts, human embyronic stem cells, and induced pluripotent stem cells with heterozygote, homozygote A-T compared to normal samples.

2012-05-27 | E-GEOD-35347 | biostudies-arrayexpress

Increased X-ray sensitivity and sustained chromosomal stability in Ataxia Telangiectasia-derived induced pluripotent stem (AT-iPS) cells

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

Increased X-ray sensitivity and sustained chromosomal stability in Ataxia Telangiectasia-derived induced pluripotent stem (AT-iPS) cells

2013-06-22 | E-GEOD-47498 | biostudies-arrayexpress

Ataxia-telangiectasia cerebellar cortex expression

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

Ataxia-telangiectasia cerebellar cortex expression

2015-10-30 | GSE61019 | GEO

Restoration of defective nuclear-mitochondrial DNA damage signaling suppresses neuropathology and extends healthspan in Ataxia telangiectasia across species

Project description:Ataxia-telangiectasia (A-T) is a disease characterized by genomic instability and severe neurodegeneration. It is caused by mutation in Ataxia-telangiectasia mutated gene (ATM) which encodes ATM, a key player in DNA double-strand break (DSB) repair. While many major symptoms of A-T (including hypersensitivity to ionizing radiation) are readily explained by its deficiency in repair of DSBs, the causes for the devastating cerebellar degeneration are still elusive. Here we report that in A-T, persistent unrepaired DNA damage signals from the nucleus to mitochondria (NM signaling) causing mitochondrial dysfunction leading to neurodegeneration. We find that depletion of NAD+ in A-T across species is likely due to persistent PARylation as inhibition of PARP1 restores NAD+levels.. NAD+ depletion affects the NAD+/SIRT1-PGC1α axis causing accumulation of damaged mitochondria through inhibition of mitophagy. Restoration of NAD+/SIRT1 activity through PARP1 inhibition, NAD+ supplementation or SIRT1 activation rescued the pathological and behavioral defects in A-T, suggesting a conserved role of the NAD+/SIRT1 pathway in inhibiting disease pathology. Notably, increasing the NAD+ levels extends lifespan and rescues A-T-specific behavioral defects in both C. elegans and mouse models of A-T. This is through induction of PINK1-DCT1-regulated mitophagy and DNA-PKcs-associated NHEJ DNA repair. Our results underscore the unified role of SIRT1 (Sir2.1) in mitochondrial health and highlight how Sir2.1 not only regulates mitochondrial biogenesis, but also induces PINK1-DCT1-dependent mitophagy. Our data support a model where by the two major theories on aging, DNA damage accumulation and mitochondrial dysfunction, conspire to promote neurodegeneration in A-T animal models and suggest that therapeutic interventions are possible in A-T and other untreatable DNA repair-deficient disorders.

2018-06-25 | PXD003380 | Pride

Ataxia-telangiectasia mutated (Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy

Project description:Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by inactivating p53 mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, presenting therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (Atm) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models to identify transactivation-independent p53 activity as the key mediator of such radiosensitivity.

2023-11-04 | GSE246584 | GEO

NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair.

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

Cerebellar differentiation in Ataxia-Telangiectasia

Project description:Control (CRL2429 C11) and A-T (MC3/AT30) iPSC were differentiated according to Erceg et al to generate cerebellar precursors

2017-10-02 | GSE75852 | GEO

MeDIP analysis of 5mC and 5hmC marks in human ataxia-telangiectasia cerebellum

Project description:Genomic DNA was prepared, fragmented, and immunoprecipitated with antibodies specific for 5mC or 5hmC prior to standard sequencing. 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 | GSE61133 | GEO

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