期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 11, 页码 4319-4330出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI83185
关键词
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资金
- Spanish government through the Plan Nacional de I+D+I
- Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion
- Fondo Europeo de Desarrollo Regional (FEDER) [PI11/02036, PI13/01250]
- Spanish Ministerio de Economia y Competitividad (MINECO) [SAF2008-00357, SAF2013-49108-R, SAF2014-60551-R: iRPaD]
- Generalitat de Catalunya, Departament Economia i Coneixement, Secretaria Universitats i Recerca [AGAUR 2014 SGR-1138]
- Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa'
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 HIT 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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