Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development

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• dc.contributor.author Botta Orfila, Teresaca
• dc.contributor.author Tartaglia, Gian Gaetanoca
• dc.contributor.author Michalon, Aubinca
• dc.date.accessioned 2017-11-02T11:01:57Z
• dc.date.available 2017-11-02T11:01:57Z
• dc.date.issued 2016
• dc.description.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.
• dc.description.sponsorship 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)
• dc.format.mimetype application/pdfca
• dc.identifier.citation Botta-Orfila T, Tartaglia GG, Michalon A. Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development. Cerebellum. 2016 Oct; 15(5): 599-610. DOI: 10.1007/s12311-016-0800-2
• dc.identifier.doi http://dx.doi.org/10.1007/s12311-016-0800-2
• dc.identifier.issn 1473-4222
• dc.identifier.uri http://hdl.handle.net/10230/33128
• dc.language.iso eng
• dc.publisher Springerca
• dc.relation.ispartof Cerebellum. 2016 Oct;15(5):599-610
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-55054-P
• dc.rights © Springer The final publication is available at Springer via http://dx.doi.org/10.1007/s12311-016-0800-2
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Atàxia
• dc.subject.other Síndrome del cromosoma X fràgil
• dc.subject.other Tremolor
• dc.title Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug developmentca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion