The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability.

Abstract Research on the molecular pathology of genome instability disorders has advanced our understanding of the complex mechanisms that safeguard genome stability and cellular homeostasis at large. Once the culprit genes and their protein products are identified, an ongoing dialogue develops between the research lab and the clinic in an effort to link specific disease symptoms to the functions of the proteins that are missing in the patients. Ataxi A-T elangiectasia (A-T) is a prominent example of this process. A-T’s hallmarks are progressive cerebellar degeneration, immunodeficiency, chronic lung disease, cancer predisposition, endocrine abnormalities, segmental premature aging, chromosomal instability and radiation sensitivity. The disease is caused by absence of the powerful protein kinase, ATM, best known as the mobilizer of the broad signaling network induced by double-strand breaks (DSBs) in the DNA. In parallel, ATM also functions in the maintenance of the cellular redox balance, mitochondrial function and turnover and many other metabolic circuits. An ongoing discussion in the A-T field revolves around the question of which ATM function is the one whose absence is responsible for the most debilitating aspect of A-T – the cerebellar degeneration. This review suggests that it is the absence of a comprehensive role of ATM in responding to ongoing DNA damage induced mainly by endogenous agents. It is the ensuing deterioration and eventual loss of cerebellar Purkinje cells, which are very vulnerable to ATM absence due to a unique combination of physiological features, which kindles the cerebellar decay in A-T.