Facility for drug testing in alpha-syn transgenic drosophila & new models of PD

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Drugs can modify the course of neurodegeneration in ct-synuclein transgenic Drosophila. We developed a method that can be used to test hundreds, and perhaps in the future, thousands (if candidates, allowing an unbiased approach to be taken. This approach has the advantage over the currently prevalent approach to drug discovery in that targets that are not known to be involved in Parkinsonian neurodegeneration can be identified. Our first screen, of over 650 FDA-approved drugs, turned up two classes of drugs that suppress the Parkinsonian phenotype. The fact that most (10/12) of the suppressor compound; clustered into these two groups confirms the utility of Drosophila as a model for drug testing. Neither of these classes was expected to have activity, based on the current literature. This result demonstrates the power of the method for generating new hypotheses concerning PD pathogenesis. Members of each drug class have been demonstrated to protect mammalian neuroblastoma cells against alpha-synuclein toxicity, supporting the relevance of Drosophila for studying mammalian disease. The core B component of our Udall Center will support continued drug testing and the addition of studies aimed at probing the influence of dietary fats on PD. In addition, we plan to make this methodology available to investigators in other Udall centers, both for the execution of specific experiments, and for the training of their own scientists. This core will be a unique resource for PD research.