Drug_FXSPreMut

The Fragile X gene (FMR1) is polymorphic for the number of CGG trinucleotide repeats in its 5’-untranslated region. Repeat sizes in the general population range between 5-55 CGG repeats. In Fragile X syndrome repeat expansions exceed 200, silencing expression of FMR1, resulting in intellectual disability. Carriers of the Fragile X premutation have between 55-200 repeats in the FMR1 gene and are at risk for developing Fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a late onset neurodegenerative disorder causing tremor, ataxia, brain pathology, cognitive loss, dementia and early death in some individuals. The proposed pathological mechanism is a toxic RNA gain-of-function model in which mRNAs containing expanded CGG repeats accumulate in neuronal nuclear aggregates. These RNA aggregates sequester specific RNA-binding proteins, thus impairing their normal cellular functions and ultimately resulting in neuronal death. Currently, no treatment exists for FXTAS. As the potential molecular target is well defined (i.e. the mutant FMR1 mRNA), FXTAS is highly amenable to the development of gene targeting therapy. Therefore, the primary objective of this proposal is (1) to establish critical developmental periods when disease might be halted or reversed and (2) to identify pharmacological and molecular compounds to alleviate expanded CGG-induced toxicity. Collectively, the partners of this multidisciplinary consortium have excellent in vivo and in vitro models of FXTAS, valuable resources and state-of-the-art and emerging technologies available.