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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.