Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects the carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Common features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline. The neuropathological hallmarks of FXTAS include ubiquitin-positive intranuclear inclusions throughout brain and marked dropout of Purkinje neurons in cerebellum. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS, and develop effective therapeutic interventions for FXTAS. Several lines of evidence, including our findings from both Drosophila and mouse models, support an RNA (fragile X premutation rCGG repeats)-mediated gain-of-function toxicity model for FXTAS, in which rCGG repeat-binding proteins (RBPs) become functionally limited through sequestration by lengthy rCGG repeats. Our previous work has identified two known RNA-binding proteins, Pur and hnRNP A2/B1, as RBPs. We showed that both proteins could modulate rCGG-mediated toxicity, supporting the RNA-mediated sequestration model of FXTAS. Using the translating ribosome affinity purification (TRAP) approach, we have also found that the expression of TDP-43 is significantly reduced in young mouse Purkinje neurons expressing rCGG repeats and that TDP-43 levels can modulate rCGG repeat-mediated toxicity in our FXTAS Drosophila model. Also unexpectedly we found that hnRNP A2/B1 can affect epigenetic modulation through interacting with Tet2, a member of Tet family proteins that converts 5- methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In this proposal, we plan to continue to use both Drosophila and mouse models to further test the hypothesis that FXTAS results from abnormal RNA metabolism that stems from inappropriate association of RBPs with the RNA produced by FMR1 premutation alleles, and to explore the role of 5hmC-mediated epigenetic modulation in FXTAS pathogenesis. Successful completion of these studies should significantly advance our understanding the molecular pathogenesis of FXTAS. Identifications of genes and pathways involved in FXTAS will provide valuable targets for future pharmacological research aimed at developing drugs for therapy.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects the carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The long-term goal of this project is to understand the molecular pathogenesis of FXTAS, and develop effective therapeutic interventions for FXTAS. Here we will use both Drosophila and mouse models to test the hypothesis that FXTAS results from abnormal RNA metabolism that stems from inappropriate association of RBPs with the RNA produced by FMR1 premutation alleles.
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