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Title: Targeting CAG repeat RNAs reduces Huntington's disease phenotype independently of huntingtin levels
Author: Rué Cabré, Laura
Bañez-Coronel, Mónica
Creus Muncunill, Jordi
Giralt Torroella, Albert
Alcalá Vida, Rafael
Mentxaka, Gartze
Kagerbauer, Birgit
Zomeño Abellán, M.Teresa
Aranda, Zeus
Venturi, Verónica
Pérez Navarro, Esther
Estivill, Xavier, 1955-
Martí, Eulàlia
Keywords: Corea de Huntington
Malalties neurodegeneratives
Huntington's chorea
Neurodegenerative diseases
Issue Date: 1-Nov-2016
Publisher: American Society for Clinical Investigation
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.
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It is part of: Journal of Clinical Investigation, 2016, vol. 126, num. 11, p. 4319-4330
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ISSN: 0021-9738
Appears in Collections:Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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