Genetic Analysis of Ataxia-telangiectasia

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DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a recessive genetic disorder associated with progressive neurodegeneration. The gene responsible for A-T, ATM (A-T mutated) encodes a protein kinase that plays a central role in the response to DNA damage in humans and other animals, including Drosophila. Cells derived from A-T patients exhibit chromosomal instability and hypersensitivity to DNA damaging agents. ATM responds to DNA damage by phosphorylation of proteins that regulate the DNA repair, cell cycle, and apoptosis machineries. Despite these advances in our understanding of ATM activities, there is not convincing explanation for how ATM protects neurons from degeneration. Furthermore, there is no whole animal system to study degeneration of ATM-deficient neurons. These shortfalls have prevented the development of therapies for the most debilitating clinical manifestation of A-T, neuromotor dysfunction. We hypothesize that heterozygous mutations of unknown genes contributes to neurodegeneration in A-T. Mutation of different genes would explain the variability in the onset and severity of neurodegeneration in A-T patients. Theoretically, a genetic background may exist that wholly compensates for the role ATM plays in protecting neurons from degeneration. Thus, the short-term goal of this project is to identify genes that alter the severity of degeneration of ATM-deficient neurons. To achieve this goal, we have established a Drosophila A-T model that mimics features of neurodegeneration in A-T patients. We will use this model to screen for genes that , when mutated, suppress or enhance the neurodegeneration phenotype. Follow- up studies in flies and mammalian cells will be aimed at understanding the cellular and molecular basis for how the identified genes modulate degeneration of ATM-deficient neurons. These findings will help us achieve our long-term goal of identifying drugs or other therapeutic approaches that protect neurons from degeneration in A-T. This multidisciplinary study will be a collaborative effort between the Wassarman and Tibbetts laboratories. To our knowledge, this study represents the first effort to use a whole animal model to determine modifiers of ATM activity in the nervous system.Ataxia-telangiectasia (A-T) is a recessive genetic disorder associated with progressive neurodegeneration. We have established a Drosophila A-T model that mimics features of neurodegeneration in A-T patients. Using this model we propose to identify gene targets for therapeutic approaches that protect neurons from degeneration in A-T.