We propose to identify drugs that prevent neurodegeneration in the human disease Ataxia-telangiectasia (A-T). A-T is a rare genetic disease characterized by ataxia, a lack of motor coordination. Neurodegenerative events in the cerebellum that bring about the ataxia begin before the age of two and get worse with age, resulting in wheelchair dependence between the ages of eight and twelve. Research into the causes of neurodegeneration began in earnest in 1995 when the defective gene A-T mutated (ATM) was identified. However, despite considerable progress in understanding ATM functions in normal cells and cellular processes that are dysregulated in ATM mutant cells, no therapies have been developed that prevent neurodegeneration. A major barrier to the development of therapies has been the lack of animal models of A-T that undergo neurodegeneration. We have created fruit fly (Drosophila melanogaster) models of A-T. The fly models recapitulate the progressive neurodegeneration that occurs in A-T patients. Using these models, we have developed assays that can serve to measure the effectiveness of drugs in preventing neurodegeneration. We have also identified molecular events such as neuron cell cycle reentry and glial cell innate immune response activation that cause neurodegeneration, making these events high priority targets for drug therapy. Flies are well-suited for identifying drugs that are effective in the multicellular context of whole animals. The small size and short lifespan of flies make it possible to carry out screens of thousands of drugs. Drugs can be placed in fly food, flies eat the food, and neurodegeneration can be measured at points throughout the fly lifespan. In addition, although many aspects of fly and human development and physiology are quite different, the underlying molecular details are often very similar. So, drugs that are effective in flies have a reasonable probability of being effective in humans. To achieve the goal of identifying drugs that prevent neurodegeneration in A-T, we propose to screen 2,320 bioactive drugs for the ability to suppress the rough eye phenotype caused by ATM knockdown in the eye and the developmental lethality phenotype caused by an endogenous ATM mutation.
Ataxia-telangiectasia (A-T) is a human neurodegenerative disease. Our studies in fruit flies, Drosophila melanogaster, have uncovered novel pathways of molecular events that cause neurodegeneration in A-T. The proposed research will build upon these findings to accomplish the goal of preventing neurodegeneration in A- T and other diseases.