Research Grant Award

David A. Wassarman

University of Wisconsin-Madison
A Drosophila Model of Ataxia-Telangiectasia

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 hypersensivity 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 no 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 debilitation clinical manifestation of A-T neuromotor dysfunction.

The goal of this project is to identify genes that work in partnership with ATM to protect neurons from regeneration. While much has been learned about how the ATM protein functions in cells with DNA damage, there in no convincing explanation for why loss of the ATM protein leads to neurodegeneration. We have chosen to address this issue by using the power of fruit fly genetics. We have created flies in which neurodegeneration occurs in the fly eye as a consequence of reduced levels of ATM. We have found that the severity of neurodegeneration is sensitive to mutations in genes that function while mutant genes that reduce the severity of neurodegeneration would be expected to encode proteins that promote degeneration of neurons with reduced ATM function. A preliminary screen of 650 mutants has identified known components of the ATM signaling pathway that responds to DNA damage as suppressors of the ATM RNAi phenotype, validating this approach for understanding the genetic basis of A-T. We propose to continue this screen to identify the complete roster of genetics that modify the ability of ATM to protect neurons from degeneration. The study is significant because it may define targets for drugs that prevent neuron loss in A-T.