The failure to respond to DNA damage can result in a variety of human diseases, many of which impact the nervous system leading to neurodegeneration, microcephaly or brain tumors. DNA repair defects have also been linked to aging and age-related neurodegenerative syndromes such as Alzheimer's and Parkinson's disease. An ever-increasing group of DNA repair-deficient neurological syndromes reflect the key roles played by multiple DNA repair pathways to maintain neural homeostasis. The neurodegenerative syndrome ataxia telangiectasia (A-T), which results from loss of function of the DNA damage-signaling serine/threonine kinase ATM (ataxia telangiectasia, mutated), exemplifies the importance of genome stability in the nervous system. However, despite intense interest in the molecular details of ATM function, its role in the nervous system remains elusive. Little is known about the key substrates or regulation of ATM in an in vivo neural setting. We have uncovered a pathogenic DNA lesion that may underpin the disease etiology in A-T. We found that ATM is critical for preventing DNA lesions resulting from the accumulation of topoisomerase-1-DNA cleavage complexes and subsequently DNA strand breaks that arise when replicating DNA or transcription encounter these complexes. In this grant proposal we plan experiments to delineate the connections between Atm signaling and topoisomerase-1 function. An additional issue hampering A-T research has been the lack of a suitable model for A-T; while inactivation of murine Atm mirrors the extraneurological A-T phenotype, it does not recapitulate ataxia or neurodegeneration. We have now developed unique mouse models for A-T in which overt ataxia results from loss of Atm, in a similar manner to the human disease. Using these models we propose to undertake experiments that will delineate the biochemistry and pathophysiology that underpins this disease. Finally, we have also identified a new regulator of Atm function that modulates Atm activation in the brain. We propose experiments to further our studies of this regulatory kinase to explore the mechanistic basis of Atm control. In combination, experiments outlined in this proposal will provide critical new information about the etiology of A-T, and they will be important for the development of therapeutic approaches to treat neurological disease resulting from genome instability.
A multitude of human syndromes showing profound neurological defects such as neurodegeneration or brain tumors can result from inherited mutations in DNA repair factors. These syndromes illustrate the importance of DNA repair for brain development. Understanding how the DNA repair pathways function during both brain development and in the mature brain is critical for the development of treatments for these diseases. This grant application proposes a number of novel approaches to investigate how specific DNA repair pathways prevent brain disease.
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