Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system

摘要

Ataxia-telangiectasia is a hereditary multisystemic disease result- ing from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation. The molecular details of ATM function in the nervous system are unclear, although the neuro- Iogical lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin. The central nervous sys- tem (CNS) of Atm-null mice shows a pronounced defect in apo- ptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage. Here. we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (lR). Although many of the same regions of the CNS in both Bax-/- and Atm-/- mice were radioresistant. mice nullizy- gous for both Bax and Atm showed additional reduction in lR- induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Further, Atm- and Bax-dependent apo- ptosis in the CNS also required caspase-3 activation. These data implicate Bax and caspase-3 as death effectors in neurodegenera- tive pathways.