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Cell Death and Differentiation Oct 2019Ataxia telangiectasia (AT) is a genetic disease caused by mutations in the ATM gene but the mechanisms underlying AT are not completely understood. Key functions of the...
Ataxia telangiectasia (AT) is a genetic disease caused by mutations in the ATM gene but the mechanisms underlying AT are not completely understood. Key functions of the ATM protein are to sense and regulate cellular redox status and to transduce DNA double-strand break signals to downstream effectors. ATM-deficient cells show increased ROS accumulation, activation of p38 protein kinase, and increased levels of DNA damage. GSE24.2 peptide and a short derivative GSE4 peptide corresponding to an internal domain of Dyskerin have proved to induce telomerase activity, decrease oxidative stress, and protect from DNA damage in dyskeratosis congenita (DC) cells. We have found that expression of GSE24.2 and GSE4 in human AT fibroblast is able to decrease DNA damage, detected by γ-H2A.X and 53BP1 foci. However, GSE24.2/GSE4 expression does not improve double-strand break signaling and repair caused by the lack of ATM activity. In contrast, they cause a decrease in 8-oxoguanine and OGG1-derived lesions, particularly at telomeres and mitochondrial DNA, as well as in reactive oxygen species, in parallel with increased expression of SOD1. These cells also showed lower levels of IL6 and decreased p38 phosphorylation, decreased senescence and increased ability to divide for longer times. Additionally, these cells are more resistant to treatment with H0 and the radiomimetic-drug bleomycin. Finally, we found shorter telomere length (TL) in AT cells, lower levels of TERT expression, and telomerase activity that were also partially reverted by GSE4. These observations suggest that GSE4 may be considered as a new therapy for the treatment of AT that counteracts the cellular effects of high ROS levels generated in AT cells and in addition increases telomerase activity contributing to increased cell proliferation.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line; DNA Breaks, Double-Stranded; DNA Damage; Fibroblasts; Humans; Nanoparticles; Nuclear Proteins; Oxidative Stress; Peptide Fragments; Phosphorylation; Reactive Oxygen Species; Telomerase; Telomere
PubMed: 30670828
DOI: 10.1038/s41418-018-0272-7 -
International Journal of Molecular... Dec 2022ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in...
ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients-and classified by in silico tools as pathogenic, uncertain significance, or benign-using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.
Topics: Humans; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; DNA Copy Number Variations; Loss of Heterozygosity; Melanoma
PubMed: 36555667
DOI: 10.3390/ijms232416027 -
Developmental Dynamics : An Official... Jan 2018Ataxia-telangiectasia (A-T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A-T is... (Review)
Review
Ataxia-telangiectasia (A-T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A-T is attributed to the deficiency of the protein kinase coded by the ATM (ataxia-telangiectasia mutated) gene. ATM is a sensor of DNA double-strand breaks (DSBs) and signals to cell cycle checkpoints and the DNA repair machinery. ATM phosphorylates numerous substrates and activates many cell-signaling pathways. There has been considerable debate about whether a defective DNA damage response is causative of the neurological aspects of the disease. In proliferating cells, ATM is localized mainly in the nucleus; however, in postmitotic cells such as neurons, ATM is mostly cytoplasmic. Recent studies reveal an increasing number of roles for ATM in the cytoplasm, including activation by oxidative stress. ATM associates with organelles including mitochondria and peroxisomes, both sources of reactive oxygen species (ROS), which have been implicated in neurodegenerative diseases and aging. ATM is also associated with synaptic vesicles and has a role in regulating cellular homeostasis and autophagy. The cytoplasmic roles of ATM provide a new perspective on the neurodegenerative process in A-T. This review will examine the expanding roles of ATM in cellular homeostasis and relate these functions to the complex A-T phenotype. Developmental Dynamics 247:33-46, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Homeostasis; Humans; Mitochondria; Nerve Degeneration; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 28543935
DOI: 10.1002/dvdy.24522 -
Journal of Clinical Pathology Oct 2005Ataxia telangiectasia (A-T) is one of a group of autosomal recessive cerebellar ataxias. Presentation is usually by the age of 2 years and ataxia of both upper and lower... (Review)
Review
Ataxia telangiectasia (A-T) is one of a group of autosomal recessive cerebellar ataxias. Presentation is usually by the age of 2 years and ataxia of both upper and lower limbs develops, such that by early teenage most patients require a wheelchair for mobility. Speech and eye movement are also affected. Other important features are t(7;14) translocations, immunodeficiency, a high serum alpha fetoprotein concentration, growth retardation, telangiectasia-most noticeably on the bulbar conjunctiva-and a very high risk of developing a lymphoid tumour. Patients also show an increased sensitivity to ionising radiation. The classic form of A-T results from the presence of two truncating ATM mutations, leading to total loss of the ATM protein, a protein kinase. Importantly, A-T shows clinical heterogeneity, including milder forms where neurological progression may be slower or of later onset. In these cases there is a correlation between the preservation of neurological function, decreased radiosensitivity, and the degree of retained ATM protein kinase activity. Considerable scope remains for understanding the progress of the disorder in relation to the types of ATM mutation present.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA-Binding Proteins; Genotype; Humans; Mutation; Neoplasms; Phenotype; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 16189143
DOI: 10.1136/jcp.2005.026062 -
Blood Cells, Molecules & Diseases Jan 2014The ability of hematopoietic stem cells (HSCs) to self-renew and differentiate into progenitors is essential for homeostasis of the hematopoietic system. The longevity... (Review)
Review
The ability of hematopoietic stem cells (HSCs) to self-renew and differentiate into progenitors is essential for homeostasis of the hematopoietic system. The longevity of HSCs makes them vulnerable to accumulating DNA damage, which may be leukemogenic or result in senescence and cell death. Additionally, the ability of HSCs to self-renew and differentiate allows DNA damage to spread throughout the hematologic system, leaving the organism vulnerable to disease. In this review we discuss cell fate decisions made in the face of DNA damage and other cellular stresses, and the role of reactive oxygen species in the long-term maintenance of HSCs and their DNA damage response.
Topics: Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; BH3 Interacting Domain Death Agonist Protein; Cell Differentiation; Cell Proliferation; DNA Damage; Gene Expression Regulation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Oxidation-Reduction; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction
PubMed: 24041596
DOI: 10.1016/j.bcmd.2013.08.002 -
PloS One 2018Ataxia telangiectasia (A-T) is an incurable and rare hereditary syndrome. In recent times, treatment with glucocorticoid analogues has been shown to improve the...
Ataxia telangiectasia (A-T) is an incurable and rare hereditary syndrome. In recent times, treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this condition, but the molecular mechanism of action of these analogues remains unknown. Hence, the aim of this study was to gain insight into the molecular mechanism of action of glucocorticoid analogues in the treatment of A-T by investigating the role of Dexamethasone (Dexa) in A-T lymphoblastoid cell lines. We used 2DE and tandem MS to identify proteins that were influenced by the drug in A-T cells but not in healthy cells. Thirty-four proteins were defined out of a total of 746±63. Transcriptome analysis was performed by microarray and showed the differential expression of 599 A-T and 362 wild type (WT) genes and a healthy un-matching between protein abundance and the corresponding gene expression variation. The proteomic and transcriptomic profiles allowed the network pathway analysis to pinpoint the biological and molecular functions affected by Dexamethasone in Dexa-treated cells. The present integrated study provides evidence of the molecular mechanism of action of Dexamethasone in an A-T cellular model but also the broader effects of the drug in other tested cell lines.
Topics: Ataxia Telangiectasia; Blotting, Western; Cell Line; Dexamethasone; Gene Expression Profiling; Gene Expression Regulation; Glucocorticoids; Humans; Microarray Analysis; Proteome; Proteomics; Transcriptome
PubMed: 29608596
DOI: 10.1371/journal.pone.0195388 -
Stem Cell Research Sep 2016Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases....
Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases. Previous studies revealed low reprogramming efficiency from A-T and carrier fibroblasts, a barrier to iPS cell-based modeling and regeneration. Here, we tested the feasibility of employing circulating erythroid cells, a compartment no or minimally affected in A-T, for the generation of A-T and carrier iPS cells. Our results indicate that episomal expression of Yamanaka factors plus BCL-xL in erythroid cells results in highly efficient iPS cell production in feeder-free, xeno-free conditions. Moreover, A-T iPS cells generated with this protocol maintain long-term replicative potential, stable karyotypes, re-elongated telomeres and capability to differentiate along the neural lineage in vitro and to form teratomas in vivo. Finally, we find that haploinsufficiency for ATM does not limit reprogramming from human erythroid cells or in vivo teratoma formation in the mouse.
Topics: Adolescent; Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Base Sequence; Cell Differentiation; Cell Line; Cell Lineage; Cellular Reprogramming; DNA Mutational Analysis; Erythroid Cells; Fluorescent Antibody Technique, Indirect; Humans; Induced Pluripotent Stem Cells; Karyotype; Male; Mice; Mice, Inbred C57BL; Neural Stem Cells; Telomere; Telomere Shortening; Teratoma; Transcription Factors
PubMed: 27596957
DOI: 10.1016/j.scr.2016.08.006 -
PloS One 2018Classic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid...
INTRODUCTION
Classic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid malignancies and telangiectasias. Prior studies have suggested that chronic inflammation and premature aging may contribute to the development of malignancy and pulmonary disease in people with A-T. To further examine the link between A-T and inflammation, we hypothesized that subjects with classic A-T would have greater enrichment of inflammatory pathways in peripheral blood mononuclear cells (PBMCs) compared to non A-T age-matched controls. To test this hypothesis we used RNAseq as an unsupervised approach to identify biological processes altered in people with classic A-T.
METHODS
PBMCs were isolated from subjects with classic A-T and compared to non-A-T age-matched healthy controls. RNAseq with differential gene expression analyses was then performed. Selected genes were validated by RT-qPCR using cohorts of subjects consisting of classic A-T, mild A-T or non-A-T controls. Subjects with mild A-T were characterized by later onset/mild neurologic features and normal/near normal immune status.
RESULTS
RNAseq revealed 310 differentially expressed genes (DEGs) including genes involved in inflammation, immune regulation, and cancer. Using gene set enrichment analysis, A-T subjects were found to have biological processes enriched for inflammatory and malignancy pathways. In examining a cohort of A-T subjects in which baseline serum IL8 and IL6 levels were measured previously, an association was found between higher serum IL8 levels and higher likelihood of developing malignancy and/or death in a subsequent 4-6 year period.
CONCLUSION
RNAseq using PBMCs from subjects with classic A-T uncovered differential expression of immune response genes and biological processes associated with inflammation, immune regulation, and cancer. Follow-up of A-T subjects over a 4-6 year period revealed an association between higher baseline serum IL8 levels and malignancy/death. These findings support a role for inflammation as a contributing factor in A-T phenotypes.
Topics: Adolescent; Adult; Ataxia Telangiectasia; Case-Control Studies; Child; Child, Preschool; Female; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation; Healthy Volunteers; Humans; Inflammation; Interleukin-8; Leukocytes, Mononuclear; Male; Neoplasms; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, RNA; Young Adult
PubMed: 30586396
DOI: 10.1371/journal.pone.0209496 -
Scientific Reports Nov 2023Ataxia telangiectasia is a monogenetic disorder caused by mutations in the ATM gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double...
Ataxia telangiectasia is a monogenetic disorder caused by mutations in the ATM gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double strand breaks (DSBs). Impaired function of this kinase leads to a multisystemic disorder including immunodeficiency, progressive cerebellar degeneration, radiation sensitivity, dilated blood vessels, premature aging and a predisposition to cancer. Since allogenic hematopoietic stem cell (HSC) transplantation improved disease outcome, gene therapy based on autologous HSCs is an alternative promising concept. However, due to the large cDNA of ATM (9.2 kb), efficient packaging of retroviral particles and sufficient transduction of HSCs remains challenging.We generated lentiviral, gammaretroviral and foamy viral vectors with a GFP.F2A.Atm fusion or a GFP transgene and systematically compared transduction efficiencies. Vector titers dropped with increasing transgene size, but despite their described limited packaging capacity, we were able to produce lentiviral and gammaretroviral particles. The reduction in titers could not be explained by impaired packaging of the viral genomes, but the main differences occurred after transduction. Finally, after transduction of Atm-deficient (ATM-KO) murine fibroblasts with the lentiviral vector expressing Atm, we could show the expression of ATM protein which phosphorylated its downstream substrates (pKap1 and p-p53).
Topics: Animals; Mice; Ataxia Telangiectasia; Genome, Viral; Transgenes; Genotype; Genetic Therapy
PubMed: 37938627
DOI: 10.1038/s41598-023-46332-4 -
The American Journal of Case Reports Jul 2017BACKGROUND The body of literature on oral motor and swallowing disorders in patients with ataxia telangiectasia (AT) is limited. CASE REPORT The purpose of this study...
BACKGROUND The body of literature on oral motor and swallowing disorders in patients with ataxia telangiectasia (AT) is limited. CASE REPORT The purpose of this study was to characterize oral motor and swallowing disorders in two siblings with AT, based on oral motor and swallowing assessments. Specific procedures were applied for oral motor and swallowing assessments and both patients underwent videofluoroscopy (VFS). Case 1 presented vocal instability, change in postural control during feeding; food retention in oral cavity; slower oral transit time; and multiple swallowing (signs for solid and liquid). Case 2 presented parted lips at rest and reduced muscle strength; reduced strength and mobility of the tongue; vocal weakness and instability; reduced speech precision and intelligibility; decreased intonation pattern; food retention in oral cavity during feeding; slower oral transit time; multiple swallowing (signs for solid and liquid); poor bolus ejection; incoordination and difficulty in controlling the sips of water taken from the cup; altered cervical auscultation after swallowing and respiratory distress (liquid and puree). For both patients VFS results revealed laryngeal penetration for liquid. CONCLUSIONS Although the literature describes the occurrence of dysarthria and swallowing disorders in patients with AT, little attention has been given to describing which oral motor deficits are responsible for these disorders. Early identification of swallowing alterations and rehabilitation could decrease the risk of aspiration pneumonia. Future studies are necessary in order to investigate the deterioration process of swallowing in AT and the influence of rehabilitation in maintaining functional health.
Topics: Ataxia Telangiectasia; Deglutition Disorders; Dysarthria; Female; Humans; Male; Siblings; Tongue; Voice Disorders; Young Adult
PubMed: 28698541
DOI: 10.12659/ajcr.903592