Ataxia-Telangiectasia:
A Crossroads of Genome Instability, Neurodegeneration and Accelerated Aging

The Genome instability syndromes provide striking examples of the connection between genome instability, degeneration of specific tissues, segmental premature aging and cancer predisposition. Ataxia-telangiectasia (A-T) is a prototypic genome instability syndrome, characterized by progressive cerebellar degeneration, chronic lung disease, immune deficiency, endocrine abnormalities, segmental premature aging, cancer predisposition, chromosomal fragility, and sensitivity to various DNA damaging agents, which is most pronounced when such agents cause DNA double-strand breaks (DSBs). The responsible gene, ATM, encodes the homeostatic ATM protein kinase, whose most documented role is in activating the DNA damage response (DDR) following DSB induction, but it also regulates redox balance and an array of processes involved in maintaining cellular homeostasis. Examination of the various phenotypic features of A-T vis-à-vis ATM’s many functions thus provides a broad experimental arena. We are examining the possibility of obtaining faithful mouse models and cellular systems to study two main features of A-T: the slow but relentless, progressive cerebellar atrophy, and the accelerated aging.

Some of the symptoms of the severe genome instability syndromes are mildly expressed in carriers of the corresponding mutations, with broad implications on public health. After following a cohort of A-T carriers and controls in two Israeli communities for two decades, we have come to the conclusion that heterozygosity for A-T mutations does affect aging pace and the associated maladies. These are first steps towards establishing an individual ‘genome stability index’ that will be determined according to sequence alterations in many DDR genes, and become a useful tool in predictive testing and precision medicine.