FXTAS: Mechanisms and Modifiers

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SUMMARY Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects individuals with premutation alleles (55–~200 CGG repeats) in fragile X mental retardation 1 (FMR1). Common features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline. Penetrance is age-dependent and reaches ~75% in male carriers by age 80. Up to ~15% of women with premutations also show symptoms of FXTAS. The neuropathological hallmarks of FXTAS include ubiquitin- positive intranuclear inclusions throughout the brain and marked dropout of Purkinje neurons in the cerebellum. At the molecular level, FMR1 premutation alleles exhibit a 2 to 8-fold increase in FMR1 mRNA and expression of mutant mRNAs containing long (~100) CGG triplets has been shown to be toxic in cell and animal models. Current data support two non-mutually exclusive molecular pathogenesis mechanisms for FXTAS: 1) RNA gain- of-function, in which the expression of expanded CGGs in RNA (rCGG) interferes with a subset of RNA-binding proteins (RBPs), functionally limiting their availability through sequestration, and 2) Repeat-associated non-AUG (RAN) translation, whereby translation through the rCGG (and/or antisense rCCG) repeats leads to the production of toxic homo-polypeptides, the most abundant of which is FMRpolyGlycine (FMRpolyG), that in turn interfere with cellular functions. Multiple mouse models have been developed and used by us and others to study these mechanisms. Previous work by the Nelson, Todd, Allen and Jin groups using model organisms (flies, mice) and cell models has identified several RBPs affected by expression of rCGGs. Among these are Pur α, hnRNP A2/B1, DROSHA/DGCR8, and TDP43. Increasing expression of these proteins can modulate rCGG-mediated toxicity in model systems, supporting the RNA-mediated sequestration model of FXTAS. In addition, RAN translation products are found in patient inclusions and mouse models and appear to also confer toxicity in numerous studies. In studies to determine the contributions of both the RAN translation and RBP sequestration mechanisms to FXTAS pathogenesis, we have generated transgenic lines of mice that express hnRNP A2/B1 and suppression of rCGG repeat-mediated toxicity without alteration of FMRpolyG positive inclusions. Parallel efforts at the Emory Fragile X Center used whole genome sequence (WGS) analysis of premutation carriers with early or late onset of FXTAS, combined with fly genetic screens to identify additional genetic modifiers that influence age of onset of FXTAS. Understanding the role of variation in these genes could suggest candidate therapeutic targets. In this application, we propose to confirm and extend identification of genetic modifiers through sequence analysis and analyze potential modifiers of FXTAS identified at Emory using human genetics and model system studies at Baylor, Emory and Michigan using additional fly, cell and mouse models. In coordination with Projects 1 and 3, we expect to improve understanding of mechanisms that lead to FXTAS and other Fragile X-associated Disorders, such as Fragile X associated Primary Ovarian Insufficiency (FXPOI).