Irradiation-Induced Neuronal Apoptosis in Ataxia-Telangiectasia Protein-Deficient Mice and the Role of Caspase-3
Murray, Michael R., 1975-
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Cell death pathways were investigated in the neurodegenerative disease Ataxia Telangiectasia (A-T) using murine knockout models by measuring caspase-3 activity. Earlier this year the McKinnon Laboratory reported that apoptosis in certain areas of the developing mouse central nervous system (CNS) were shown to be reduced in mice deficient for the Atm protein following irradiation (Herzog et al., 1998). Further investigation of the Atm-dependent death pathways was done by measuring caspase-3 activity using a fluorogenic peptide. The presence of active caspase-3 is necessary for apoptosis to occur and was used to measure the differences in levels of cell death. Tissue from postnatal day five mice, six hours following irradiation were used to evaluate caspase-l (ICE) and caspase-3 (CPP32) activity in tissues lysates. It was confirmed that caspase-3 activity correlates with the levels of apoptosis observed. We showed that tissue specific responses to irradiation induced apoptosis in Atm mice reported earlier by the McKinnon Laboratory also correlate with levels of caspase-3 present following irradiation (Herzog et al., 1998). The differences in response to irradiation were further investigated by monitoring caspase activity in Bax and p53 knockout mice, whose proteins that act downstream of Atm and are part of the apoptosis pathways. The disruption of caspase-3 activities in Atm, Bax, and p53 protein deficient mice support the earlier evidence for Atm-dependent apoptosis pathways in the CNS by further revealing involvement of Atm in death signals that trigger caspase-3 activation.