A CHEMICAL LIBRARY SCREEN FOR POTENTIAL FRAGILE X THERAPEUTICA

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Variation in the length of the CGG-repeat in the FMR1 gene is now appreciated to result in at least three distinct disorders: premature ovarian failure, fragile X-associated tremor/ataxia syndrome (FXTAS), and the classic fragile X syndrome. The former two phenotypes are associated with premutation alleles of 55-200 repeats while fragile X syndrome is due to repeat expansion beyond 200 repeats. This project had initially focused upon the premutation phenotype of FXTAS, successful gaining considerable mechanistic insight into this disorder. For this renewal, the project's emphasis will shift from FXTAS to an effort to identify and characterize drugs and other small molecules as potential lead compounds for future therapeutic trials in fragile X syndrome. The reasons for this shift in emphasis are two-fold. First, much of our progress on FXTAS has been due to the work of Dr. Peng Jin, at the time a fellow in the Pi's laboratory. Now, as an independent faculty member at Emory, the PI has allowed Dr. Jin to take this project into his own laboratory. Dr. Jin has now obtained two NIH RO1 awards to continue this effort (R01NS05163002 "Molecular basis of rCGG-mediated neurodegeneration" and R01MH07609002 "Dissecting the molecular basis of fragile X syndrome in Drosophila"). Thus this Fragile X Center successfully seeded a new independent and now funded investigator into the fragile X field. Second, a stated emphasis for Fragile X Centers is the development and use of animal models to test existing medications and develop new psychopharmacologic medications. Accordingly, we have shifted emphasis of this proposal to drug development. We have had recent success with an unfunded effort to screen for drugs that rescue the dfmrl deficiency in Drosophila and have also discovered abnormal AMPA receptor trafficking due to Fmr1 deficiency in mammalian hippocampal neurons that we feel will also provide an outstanding model system for drug screening. We now propose three specific aims to further develop the Drosophila and hippocampal neuron assays as drug screening approaches and to identify and characterize novel compounds as potential therapeutics for fragile X syndrome. The results of this study will identify compounds able to rescue FMRP-deficient phenotypes in two model systems for fragile X syndrome. The Drosophila model has the advantage of detecting diverse neuronal pathways and circuits that rescue phenotypes in an intact animal. The hippocampal neuron model has the advantages of being mammalian and also detecting the rescue of a fundamental deficit in synaptic strength due to abnormal AMPAR trafficking. Together, these screens should identify a subset of compounds able to rescue phenotypes in the Fmr1 knockout mouse and therefore provide lead compounds with substantial therapeutic potential for drug development for fragile X syndrome.