Fragile X-associated Tremor/Ataxia Syndrome: RNA or RAN?

Since the discovery of the fragile X-associated tremor/ataxia syndrome (FXTAS), a large number of studies have been performed in order to identify the underlying disease mechanism(s). Two disease mechanisms for FXTAS have been proposed. The first hypothesis is an RNA gain-of-function mechanism in which the FMR1 RNA, containing an expanded CGG repeat, sequesters RNA-binding proteins. A second proposed mechanism is a repeat-associated non-AUG-initiated (RAN) protein gain-of-function mechanism in which the FMR1 RNA, containing an expanded repeat, triggers RAN translation of a cryptic polyglycine-containing protein, FMRpolyG. Gaining more mechanistic insight is essential to develop potential targets for future therapeutic intervention studies and to identify new reliable biomarkers.

The general aim of this thesis is to advance our understanding of the molecular mechanisms underlying toxicity of both RNA and RAN in FXTAS using new cellular and FXTAS mouse models. To date, no targeted treatments exist for FXTAS. Thus translational research using mouse and cellular models, as generated and characterized in this thesis, will provide the critical information needed for the development and evaluation of effective therapeutic interventions for FXTAS.