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...

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Detalles Bibliográficos
Autores: Botta Orfila, Teresa, Tartaglia, Gian Gaetano, Michalon, Aubin
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2016
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/33128
Acceso en línea:http://hdl.handle.net/10230/33128
http://dx.doi.org/10.1007/s12311-016-0800-2
Access Level:acceso abierto
Palabra clave:Atàxia
Síndrome del cromosoma X fràgil
Tremolor
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spelling Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug developmentBotta Orfila, TeresaTartaglia, Gian GaetanoMichalon, AubinAtàxiaSíndrome del cromosoma X fràgilTremolorFragile 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.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)Springer201720172016info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/33128http://dx.doi.org/10.1007/s12311-016-0800-2reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésCerebellum. 2016 Oct;15(5):599-610info:eu-repo/grantAgreement/EC/FP7/309545info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206info:eu-repo/grantAgreement/ES/1PE/BFU2014-55054-P© Springer The final publication is available at Springer via http://dx.doi.org/10.1007/s12311-016-0800-2info:eu-repo/semantics/openAccessoai:recercat.cat:10230/331282026-05-29T05:05:01Z
dc.title.none.fl_str_mv Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
title Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
spellingShingle Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
Botta Orfila, Teresa
Atàxia
Síndrome del cromosoma X fràgil
Tremolor
title_short Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
title_full Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
title_fullStr Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
title_full_unstemmed Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
title_sort Molecular pathophysiology of fragile x-associated tremor/ataxia syndrome and perspectives for drug development
dc.creator.none.fl_str_mv Botta Orfila, Teresa
Tartaglia, Gian Gaetano
Michalon, Aubin
author Botta Orfila, Teresa
author_facet Botta Orfila, Teresa
Tartaglia, Gian Gaetano
Michalon, Aubin
author_role author
author2 Tartaglia, Gian Gaetano
Michalon, Aubin
author2_role author
author
dc.subject.none.fl_str_mv Atàxia
Síndrome del cromosoma X fràgil
Tremolor
topic Atàxia
Síndrome del cromosoma X fràgil
Tremolor
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/33128
http://dx.doi.org/10.1007/s12311-016-0800-2
url http://hdl.handle.net/10230/33128
http://dx.doi.org/10.1007/s12311-016-0800-2
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cerebellum. 2016 Oct;15(5):599-610
info:eu-repo/grantAgreement/EC/FP7/309545
info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
info:eu-repo/grantAgreement/ES/1PE/BFU2014-55054-P
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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