The neurological phenotype of ataxia-telangiectasia: Solving a persistent puzzle
Section snippets
The disease
Ataxia-telangiectasia (A-T; MIM #208900) is a human autosomal recessive disorder with a complex and variable phenotype that affects several body systems and tissues [1], [2], [3], [4], [5], [6], [7], [8]. It is caused by null mutations in the ATM gene [9], [10], which encodes the protein kinase ATM, the master regulator of the cellular responses to double strand breaks (DSBs) in the DNA [11], [12], [13], [14]. A-T demonstrates the typical consequences of defects in the DNA damage response
Is the neurological phenotype of A-T caused by a DDR defect?
A conceptual difficulty has accompanied the attempts to link ATM function to the neurodegeneration in A-T. ATM has been investigated mainly in cultured proliferating cells, in which an important role of the DNA damage response is to activate the cell cycle checkpoints [11], [16], [73]. These important pathways were conceived as irrelevant to post-mitotic cells such as neurons. It was further suggested that ATM was cytoplasmic in human and murine neuronal tissues and hence functioning in
The ATM-mediated DDR in neurons
The importance of maintaining genomic stability in neurons cannot be over-emphasized and in retrospect should not have been doubted. Their finite number, long life, high metabolic rate, and continuous exposure to oxidative stress on the one hand, and extensive transcriptional activity on the other hand, call for stringent control of their genomic integrity. Nevertheless, it is expected that the DDR of post-mitotic cells will differ in certain respects from that of proliferating cells, e.g.,
Recapitulation of the A-T neurological phenotype in the mouse: the failure of the ATM-knockout mouse and the success of the Nbs1–CNS–del model
A major tool in the investigation of a human genetic disorder is the corresponding knockout mouse, which ideally should faithfully represent the human phenotype. The ATM-knockout mouse was initially heralded as “a paradigm of ataxia-telangiectasia” [120]. However, while these mice exhibit many of the characteristics of human A-T, such as retarded growth, immunodeficiency, cancer predisposition, radiosensitivity, infertility and a cellular phenotype similar to that of A-T cells, they barely show
The role of oxidative stress in the neurological phenotype of A-T
Most of the damage inflicted on cellular DNA in body tissues in normal life is probably due not to IR or exogenous radiomimetic chemicals, but rather to normal metabolic by-products. Indeed, oxidative stress resulting from endogenous metabolism is responsible at least in part for the constitutive, low level DNA damage response often detected in cultured cells [139]. Considerable oxidative stress accompanies the intensive metabolic activity in neurons, and deregulated oxidative stress has been
Modifiers of the neurological phenotype in A-T
A-T is clearly a monogenic disorder caused by mutations in the ATM gene. However, there is remarkable phenotypic variability among patients who have null ATM alleles [2], [8], [51]. We recently reported an interesting, somewhat extreme example of this phenotypic heterogeneity in two siblings with exceedingly mild A-T [51]. While this phenotype is usually associated with residual levels of functional ATM and regulatory, missense or leaky splicing ATM mutations [5], [48], [49], [52], [53], [54],
Conclusion
Our understanding of the vulnerability of the CNS to DDR defects has recently been expanded, not least by new insights into the neurological phenotype in A-T. It is becoming evident that the lack of ATM-mediated DDR in neurons underlies this phenotype, despite inevitable differences in the DDR between neurons and proliferating cells. Major questions about A-T awaiting answers concern these differences, the mode of cell death of DNA-damaged neurons, and the identification of the missing links in
Conflict of interest
None.
Acknowledgements
Work in the laboratory of the authors is supported by The A-T Medical Research Foundation, The A-T Children's Project, The Israel Science Foundation, The Israel Cancer Research Fund, The A-T Ease Foundation, The Joint Israeli–German Program in Cancer Research, The US–Israel Binational Science Foundation, the German–Israeli Foundation for Scientific Research and Development and the Israel Ministry of Health.
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2023, Chemical Engineering JournalThe hallmarks of aging in Ataxia-Telangiectasia
2022, Ageing Research ReviewsCitation Excerpt :At the cellular level, studies of A-T patient-derived cells have demonstrated an exacerbated frequency in the levels of chromosomal translocations following radiation as well as spontaneous generation of chromosomal instability (Kojis et al., 1991; Bucher et al., 2021). In addition, A-T neurons and Atm-deficient mouse neurons reveal defective repair of DSBs and abrogated phosphorylation of ATM substrates (including H2AX-Ser139 or γH2AX, KAP1-Ser824 and CHK2-Thr68) (Carlessi et al., 2014; Stern et al., 2002; Biton et al., 2008; Dar et al., 2011; Tzur-Gilat et al., 2013; Tal et al., 2018). One intrinsic DNA damaging event that increases with aging is the reintegration of active retrotransposons – such as Long interspersed element-1 (LINE1) – into the human genome (Maxwell et al., 2011).
Alterations in epigenetic regulation contribute to neurodegeneration of ataxia-telangiectasia
2019, Chromatin Signaling and Neurological Disorders
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Present address: Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080-4990, USA.