A key question in the field of neurological diseases is that of how specific mutations support normal development of the nervous system but then cause subsequent dysfunction? For some genetic diseases this is due to accumulation of toxic products as in enzyme deficiencies. However, in many other instances the molecular mechanism is not clear. Ataxia Telangiectasia (A-T) is one such disease. A-T's hallmark is progressive global neuronal degeneration beginning in childhood. However, there are other phenotypes associated with the disease. These include immunodeficiency, hematolymphopoietic malignancies, growth retardation, incomplete sexual maturation, oculocutaneous telangiectasias, sensitivity to ionizing radiation and premature aging. We generated mice deficient in ATM (Atm-deficient mice) that recapitulate most aspects of the human disease showing neurological dysfunction, immunologic abnormalities, growth retardation, infertility due to gamete degeneration, sensitivity to ionizing radiation, lymphoreticular malignancies, and chromosomal instability (Barlow et al., 1996). We analyzed many of the pleiotropic phenotypes found in the Atm-deficient mice. We identified defects in molecular pathways which led observed pathologies and defined a role for ATM during the cell cycle response to DNA damage caused by ionizing radiation (IR), meiosis and T-cell development (Barlow et al., 1997; Barlow et al., 1996; Barlow et al., 1997; Barlow et al., 1998. However, the function of ATM in postmitotic cells is unclear. This is particularly important in that neurodegeneration is the hallmark manifestation of A-T and most neurons are post-mitotic. This proposal seeks to build on our previous studies of ATM to begin to define its function in the brain. We plan to use our Atm-deficient to identify important physiological defects of the nervous system. A major goal is to define the role of ATM in managing oxidative stress. In addition, we plan to define the localization of the protein in the nervous system to assess if subcellular localization differs depending on cell cycle status. Finally, we plan to define strategies to follow neuronal dysfunction over time in the living animal. We hope these experiments will help define the role of ATM in the brain and also allow us to correlate anatomical, molecular and physiological abnormalities in brain function. These are critical steps for defining and initiating studies of potential therapeutic strategies.
