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Title:	Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
Author:	Botta Orfila, Teresa; Tartaglia, Gian Gaetano; Michalon, Aubin
Abstract:	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.
Abstract:	Our research received funding from the European Union Seventh Framework Programme (FP7/2007-2013), through the European Research Council, under grant agreement RIBOMYLOME_ 309545 (Gian Gaetano Tartaglia), and from the Fundació La Marató de TV3 (20142731). We also acknowledge support from the Spanish Ministry of Economy and Competitiveness (BFU2011-26206 and BFU2014-55054-P) and “Centro de Excelencia Severo Ochoa 2013– 2017” (SEV-2012-0208)
Subject(s):	-Atàxia -Síndrome del cromosoma X fràgil -Tremolor
Rights:	© Springer The final publication is available at Springer via http://dx.doi.org/10.1007/s12311-016-0800-2
Document type:	Article Article - Accepted version
Published by:	Springer
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