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Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels
Laura Rué, … , Xavier Estivill, Eulàlia Martí
Laura Rué, … , Xavier Estivill, Eulàlia Martí
Published October 10, 2016
Citation Information: J Clin Invest. 2016;126(11):4319-4330. https://doi.org/10.1172/JCI83185.
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Concise Communication Neuroscience Article has an altmetric score of 109

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

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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.

Authors

Laura Rué, Mónica Bañez-Coronel, Jordi Creus-Muncunill, Albert Giralt, Rafael Alcalá-Vida, Gartze Mentxaka, Birgit Kagerbauer, M. Teresa Zomeño-Abellán, Zeus Aranda, Veronica Venturi, Esther Pérez-Navarro, Xavier Estivill, Eulàlia Martí

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Figure 4

Intrastriatal injection of LNA-CTG recovers protein levels of several striatal markers in R6/2 mice.

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Intrastriatal injection of LNA-CTG recovers protein levels of several st...
(A) Levels of specific neuronal proteins 5 days after the first intrastriatal injection of LNA-SCB into WT and R6/2 mice and LNA-CTG into R6/2 mice. Box plots represent the densitometric protein quantification normalized to actin or tubulin and expressed relative to WT mice. Representative immunoblots are shown. Data were analyzed using the Kruskal-Wallis test, providing significant differences in all cases (P < 0.05). To determine statistical post-hoc differences between pairs of groups, the Mann-Whitney U test with Bonferroni’s correction was used (n = 6–8). *P < 0.05 and **P < 0.01, compared with LNA-SCB–injected WT mice; †P < 0.05 and ††P < 0.01, compared with LNA-SCB–injected R6/2 mice. (B) Individual points show the fluorescence intensity of DARPP-32 staining along rostral-to-caudal striatal sections in WT LNA-SCB, R6/2 LNA-SCB, and R6/2 LNA-CTG mice 5 days after the first intrastriatal injection. IOD, integrated optical density. ANOVA was applied using a correlation structure for the repeated measures of each animal across 8 sections (8 repeated measures for four WT LNA-SCB–, two R6/2 LNA-SCB–, and three R6/2 LNA-CTG–injected animals). Representative images of DARPP-32 staining in each condition are shown. Scale bar: 500 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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