Molecular Pathophysiology of Fragile X-Associated Tremor/Ataxia Syndrome and Perspectives for Drug Development

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder manifesting in carriers of 55 to 200 CGG repeats in the 5′ untranslated region (UTR) of the fragile X mental retardation gene (FMR1). FXTAS is characterized by enhanced FMR1 transcription and the accumulation of CGG repeat-containing FMR1 messenger RNA in nuclear foci, while the FMRP protein expression levels remain normal or moderately low. The neuropathological hallmark in FXTAS is the presence of intranuclear, ubiquitin-positive inclusions that also contain FMR1 transcript. Yet, the complete protein complement of FXTAS inclusions and the molecular events that trigger neuronal death in FXTAS remain unclear. In this review, we present the two most accepted toxicity mechanisms described so far, namely RNA gain-of-function and protein gain-of-function by means of repeat-associated non-AUG translation, and discuss current experimental and computational strategies to better understand FXTAS pathogenesis. Finally, we review the current perspectives for drug development with disease-modifying potential for FXTAS.