Elsevier

DNA Repair

Volume 7, Issue 7, 1 July 2008, Pages 1028-1038
DNA Repair

The neurological phenotype of ataxia-telangiectasia: Solving a persistent puzzle

https://doi.org/10.1016/j.dnarep.2008.03.006Get rights and content

Abstract

Human genomic instability syndromes affect the nervous system to different degrees of severity, attesting to the vulnerability of the CNS to perturbations of genomic integrity and the DNA damage response (DDR). Ataxia-telangiectasia (A-T) is a typical genomic instability syndrome whose major characteristic is progressive neuronal degeneration but is also associated with immunodeficiency, cancer predisposition and acute sensitivity to ionizing radiation and radiomimetic chemicals. A-T is caused by loss or inactivation of the ATM protein kinase, which mobilizes the complex, multi-branched cellular response to double strand breaks in the DNA by phosphorylating numerous DDR players. The link between ATM's function in the DDR and the neuronal demise in A-T has been questioned in the past. However, recent studies of the ATM-mediated DDR in neurons suggest that the neurological phenotype in A-T is indeed caused by deficiency in this function, similar to other features of the disease. Still, major issues concerning this phenotype remain open, including the presumed differences between the DDR in post-mitotic neurons and proliferating cells, the nature of the damage that accumulates in the DNA of ATM-deficient neurons under normal life conditions, the mode of death of ATM-deficient neurons, and the lack of a major neuronal phenotype in the mouse model of A-T. A-T remains a prototype disease for the study of the DDR's role in CNS development and maintenance.

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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    Present address: Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080-4990, USA.

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