Welcome to the UPF Digital Repository

Targeting CAG repeat RNAs reduces Huntington's disease phenotype independently of huntingtin levels.

Show simple item record

dc.contributor.author Rué, Laura
dc.contributor.author Bañez Coronel, Mónica
dc.contributor.author Creus-Muncunill, Jordi
dc.contributor.author Giralt, Albert
dc.contributor.author Alcalá-Vida, Rafael
dc.contributor.author Mentxaka, Gartze
dc.contributor.author Kagerbauer, Birgit
dc.contributor.author Zomeño-Abellán, M. Teresa
dc.contributor.author Aranda, Zeus
dc.contributor.author Venturi, Veronica
dc.contributor.author Pérez-Navarro, Esther
dc.contributor.author Estivill, Xavier, 1955-
dc.contributor.author Martí, Eulàlia
dc.date.accessioned 2017-01-18T09:34:13Z
dc.date.issued 2016
dc.identifier.citation Rué L, Bañez-Coronel M, Creus-Muncunill J, Giralt A, Alcalá-Vida R, Mentxaka G et al. Targeting CAG repeat RNAs reduces Huntington's disease phenotype independently of huntingtin levels. J Clin Invest. 2016 Nov 1;126(11):4319-30. DOI: 10.1172/JCI83185
dc.identifier.issn 0021-9738
dc.identifier.uri http://hdl.handle.net/10230/27927
dc.description.abstract Huntington's disease (HD) is a polyglutamine disorder caused by a CAG expansion in the Huntingtin (HTT) gene exon 1. This expansion encodes a mutant protein whose abnormal function is traditionally associated with HD pathogenesis; however, recent evidence has also linked HD pathogenesis to RNA stable hairpins formed by the mutant HTT expansion. Here, we have shown that a locked nucleic acid-modified antisense oligonucleotide complementary to the CAG repeat (LNA-CTG) preferentially binds to mutant HTT without affecting HTT mRNA or protein levels. LNA-CTGs produced rapid and sustained improvement of motor deficits in an R6/2 mouse HD model that was paralleled by persistent binding of LNA-CTG to the expanded HTT exon 1 transgene. Motor improvement was accompanied by a pronounced recovery in the levels of several striatal neuronal markers severely impaired in R6/2 mice. Furthermore, in R6/2 mice, LNA-CTG blocked several pathogenic mechanisms caused by expanded CAG RNA, including small RNA toxicity and decreased Rn45s expression levels. These results suggest that LNA-CTGs promote neuroprotection by blocking the detrimental activity of CAG repeats within HTT mRNA. The present data emphasize the relevance of expanded CAG RNA to HD pathogenesis, indicate that inhibition of HTT expression is not required to reverse motor deficits, and further suggest a therapeutic potential for LNA-CTG in polyglutamine disorders.
dc.description.sponsorship This work was supported by the Spanish government through the Plan Nacional de I+D+I and cofunded by grants from the Instituto de Salud Carlos III (ISCIII) – Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER) (project PI11/02036, to EM, and PI13/01250, to EPN); the Spanish Ministerio de Economía y Competitividad (MINECO) (SAF2008-00357 and SAF2013-49108-R, to XE, and SAF2014-60551-R: iRPaD, to EM); and the Generalitat de Catalunya, Departament Economia i Coneixement, Secretaria Universitats i Recerca (AGAUR 2014 SGR-1138, to XE).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher American Society for Clinical Investigation
dc.relation.ispartof Journal of Clinical Investigation. 2016 Nov 1;126(11):4319-30
dc.rights © American Society for Clinical Investigation
dc.subject.other Corea de Huntington (Malaltia)
dc.subject.other Fenotip
dc.title Targeting CAG repeat RNAs reduces Huntington's disease phenotype independently of huntingtin levels.
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1172/JCI83185
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2008-00357
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-49108-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-60551-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Search DSpace


Advanced Search

Browse

My Account

Statistics

In collaboration with Compliant to Partaking