Experimental Approaches Towards Therapeutic Interventions for Fragile X-associated Tremor and Ataxia Syndrome

Fragile X-associated Tremor and Ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused a expanded CGG-repeat in the 5'-UTR region of the FMR1 gene. FXTAS is hypothesized to be caused by either an RNA gain-of-function where RNA binding proteins bind the CGG-repeat hairpin or by an protein gain-of-function caused by an alternative translation mechanism called repeat associated non-AUG (RAN) translation. The general aim of this manuscript is to advance our knowledge of FXTAS pathogenesis and neuropathology caused by the expression of FMRpolyG and the formation of intranuclear inclusions. We generated new mouse models that allowed us to study the role of intranuclear inclusions, FMRpolyG and the role of astrocytes in the brain. In addition, we generated a new relevant cellular model that allows us to test potential therapeutic interventions. We also developed a new sandwich-ELISA to detect soluble and insoluble FMRpolyG protein levels in post-mortem FXTAS brain tissue. This ELISA allows us to accurately measure FMRpolyG levels and hopefully aid in the search for reliable biomarkers for FXTAS. Finally, we propose a new small molecule therapeutic intervention that is capable of reducing FMRpolyG protein levels in our new in vitro model as well as in our ubiquitous inducible mouse model. The results in this thesis will hopefully contribute to our search for potential biomarkers and the future development of effective targeted therapeutic interventions.