Variation in the length of the CGG-repeat in the FMR1 gene is now appreciated to result in at least threedistinct disorders: premature ovarian failure, fragile X-associated tremor/ataxia syndrome (FXTAS), and theclassic fragile X syndrome. The former two phenotypes are associated with premutation alleles of 55-200repeats while fragile X syndrome is due to repeat expansion beyond 200 repeats. This project had initiallyfocused upon the premutation phenotype of FXTAS, successful gaining considerable mechanistic insight intothis disorder. For this renewal, the project's emphasis will shift from FXTAS to an effort to identify andcharacterize drugs and other small molecules as potential lead compounds for future therapeutic trials in fragileX syndrome. The reasons for this shift in emphasis are two-fold. First, much of our progress on FXTAS hasbeen due to the work of Dr. Peng Jin, at the time a fellow in the Pi's laboratory. Now, as an independent facultymember at Emory, the PI has allowed Dr. Jin to take this project into his own laboratory. Dr. Jin has nowobtained two NIH RO1 awards to continue this effort (R01NS05163002 'Molecular basis of rCGG-mediatedneurodegeneration' and R01MH07609002 'Dissecting the molecular basis of fragile X syndrome inDrosophila'). Thus this Fragile X Center successfully seeded a new independent and now funded investigatorinto the fragile X field. Second, a stated emphasis for Fragile X Centers is the development and use of animalmodels to test existing medications and develop new psychopharmacologic medications. Accordingly, we haveshifted emphasis of this proposal to drug development. We have had recent success with an unfunded effort toscreen for drugs that rescue the dfmrl deficiency in Drosophila and have also discovered abnormal AMPAreceptor trafficking due to Fmr1 deficiency in mammalian hippocampal neurons that we feel will also provide anoutstanding model system for drug screening. We now propose three specific aims to further develop theDrosophila and hippocampal neuron assays as drug screening approaches and to identify and characterizenovel compounds as potential therapeutics for fragile X syndrome.The results of this study will identify compounds able to rescue FMRP-deficient phenotypes in two modelsystems for fragile X syndrome. The Drosophila model has the advantage of detecting diverse neuronalpathways and circuits that rescue phenotypes in an intact animal. The hippocampal neuron model has theadvantages of being mammalian and also detecting the rescue of a fundamental deficit in synaptic strengthdue to abnormal AMPAR trafficking. Together, these screens should identify a subset of compounds able torescue phenotypes in the Fmr1 knockout mouse and therefore provide lead compounds with substantialtherapeutic potential for drug development for fragile X syndrome.
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