Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affective carriers of premutation forms of the FMR1 gene. FXTAS results in progressive development of tremor, ataxia and neuropsychological problems, including anxiety, memory impairment and dementia. Both the gene and the pathogenic trigger (RNA toxicity) responsible for FXTAS are known; therefore, this disorder represents a promising candidate for development of targeted gene therapies. Development of an effective therapy requires a thorough understanding the cellular mechanisms of the disease, identification of molecular targets for therapy, and development of novel therapeutics that can reach those targets. Project 2 proposes to develop valid mouse models of FXTAS that will allow us, in concert with Project 1, 3 and 4, to systematically explore the underlying disease mechanisms of FXTAS and to identify molecular targets for new therapies. Specifically, we will develop and use transgenic mice that are constructed to model the gene mutation that causes FXTAS (i.e., expanded CGG trinucleotide repeat). We will then use these mice to (1) define critical periods in development for disease onset, (2) identify therapeutic windows for treatment, (3) establish the potential for halting or reversing FXTAS by targeted gene therapies, and (4) test novel therapeutics in mice for their potential to prevent or reverse the development of FXTAS. We will use our existing knock-in mice with expanded CGG trinucleotide .repeats to study the development of disease in mice, and to test novel gene-targeted (i.e., antisense DMA, RNAi) and pharmacological treatments (e.g., lithium, memantine). Additional inducible (tet-on) transgenic mice models will be developed that will enable us to turn off activation of the mutant CGG trinucleotide repeat during development to establish when suppression of abnormal gene expression can halt or reverse disease progression, as well as identify the specific cell types and mechanisms that cause FXTAS. This project, in concert with the other projects within this Consortium, will generate the essential knowledge about the causes of and potential treatments for FXTAS that will provide the foundation for the development of treatments that can halt or reverse the disease.
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