Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs

Ataxia-telangiectasia (A-T) is characterized by a markedly increased sensit ivity to ionizing radiation, increased incidence of cancer, and neurodegene ration, especially of the cerebellar Purkinje cells. Ionizing radiation oxi dizes macromolecules and causes tissue damage through the generation of rea ctive oxygen species (ROS), We therefore hypothesized that A-T is due to ox idative damage resulting from loss of function of the A-T gene product. To assess this hypothesis, we employed an animal model of A-T, the mouse with a disrupted Atm gene, We show that organs which develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebel lar Purkinje cells are particularly affected. These observations provide a mechanistic basis for the A-T phenotype and lay a rational foundation for t herapeutic intervention.