ATM and Cell Death in the Nervous System

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DESCRIPTION (provided by applicant): Many neurological diseases are characterized by the progressive loss of specific groups of neurons. The result of this neuronal loss is dysfunction of the nervous system leading to debilitating effects such as ataxia, memory deficits, epilepsy and muscular atrophy. In many cases, these syndromes underscore the important role of certain molecules responsible for the development and maintenance of the nervous system. Understanding the biology of these molecules will significantly increase our knowledge of nervous system function and will translate into positive therapeutic benefits. Ataxia telangiectasia (A-T) is a neurodegenerative disease resulting from mutations of ATM and is characterized by progressive neurodegeneration that leads to severe ataxia. We have recently found an unanticipated requirement for Atm in the response to genotoxic stress in the developing nervous system. This lead to our hypothesis that ATM is a developmental checkpoint during nervous system formation that is critical for the elimination of genomically compromised neural cells. Thus, dysfunctional ATM results in misincorporation of defective cell into the nervous system. These damaged cells will succumb to genetic lesions resulting in the progressive neurodegeneration that is a hallmark of A-T. In this application we propose experiments that will further our understanding of the important neuroprotective role of ATM by directly assessing the specificity of DNA damage signaling, the consequences of different genotoxic stresses on the form and function of the nervous system and the interrelationship of these to ATM signal transduction. The proposed studies employ an in vivo genetic approach to selectively inactivate DNA damage pathways to precisely define those that involve ATM. We will also determine the effects of chronic DNA damage in the nervous system and the contribution of Atm-dependent apoptosis to neurodegeneration. Elucidation of ATM function will be critical for understanding basic mechanisms of development and maintenance of the nervous system. These proposed experiments will be important for defining the nature of DNA lesions that occur physiologically in the nervous system and the relationship of this to neuropathological outcomes. Because many anti-neoplastic treatments involve DNA damaging agents, the results from this proposal may also have significant therapeutic implications for understanding the mechanism of action of these drugs, particularly in the treatment of brain tumors.