ArticleNucleic acids research2012
Mechanism of allele-selective inhibition of huntingtin expression by duplex RNAs that target CAG repeats: function through the RNAi pathway.
Article in Nucleic acids research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- CAG-targeting artificial miRNA with reduced off-target risk for efficient lowering of pathogenic polyglutamine proteins.NAR molecular medicine · 2026Article
- From design to cellular processing: Insights into sequencing of vectorized therapeutic small RNAs.Molecular therapy. Nucleic acids · 2024Article
- AAV-Mediated CAG-Targeting Selectively Reduces Polyglutamine-Expanded Protein and Attenuates Disease Phenotypes in a Spinocerebellar Ataxia Mouse Model.International journal of molecular sciences · 2024Article
- Haplotype-specific insertion-deletion variations for allele-specific targeting in Huntington's disease.Molecular therapy. Methods & clinical development · 2022Article
- Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS.Molecular therapy. Nucleic acids · 2021Article
- Artificial miRNAs targeting CAG repeat expansion in ORFs cause rapid deadenylation and translation inhibition of mutant transcripts.Cellular and molecular life sciences : CMLS · 2021Article
- Universal RNAi Triggers for the Specific Inhibition of Mutant Huntingtin, Atrophin-1, Ataxin-3, and Ataxin-7 Expression.Molecular therapy. Nucleic acids · 2020Article
- Limits of using oligonucleotides for allele-selective inhibition at trinucleotide repeat sequences - targeting the CAG repeat within ataxin-1.Nucleosides, nucleotides & nucleic acids · 2020Article
- Antisense Oligonucleotide Therapies for Neurodegenerative Diseases.Annual review of neuroscience · 2019Review
- Duplex RNAs and ss-siRNAs Block RNA Foci Associated with Fuchs' Endothelial Corneal Dystrophy.Nucleic acid therapeutics · 2019Article
- A potential role of extended simple sequence repeats in competing endogenous RNA crosstalk.RNA biology · 2018Article
- New developments in RAN translation: insights from multiple diseases.Current opinion in genetics & development · 2017Review
- Article
- Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53.Human molecular genetics · 2016Article
- Advances in Stem Cell Research- A Ray of Hope in Better Diagnosis and Prognosis in Neurodegenerative Diseases.Frontiers in molecular biosciences · 2016Review
- Engineering Duplex RNAs for Challenging Targets: Recognition of GGGGCC/CCCCGG Repeats at the ALS/FTD C9orf72 Locus.Chemistry & biology · 2015Article
- RAN Translation in Huntington Disease.Neuron · 2015Article
- A Tandem Oligonucleotide Approach for SNP-Selective RNA Degradation Using Modified Antisense Oligonucleotides.PloS one · 2015Article
- In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Huntington's disease is an incurable neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat within one allele of the huntingtin (HTT) gene. Agents that block expression of mutant HTT and preserve expression of wild-type HTT target the cause of the disease and are an alternative for therapy. We have previously demonstrated that mismatch-containing duplex RNAs complementary to the expanded trinucleotide repeat are potent and allele-selective inhibitors of mutant HTT expression, but the mechanism of allele selectivity was not explored. We now report that anti-CAG duplex RNA preferentially recruits argonaute 2 (AGO2) to mutant rather than wild-type HTT mRNA. Efficient inhibition of mutant HTT protein expression requires less AGO2 than needed for inhibiting wild-type expression. In contrast, inhibiting the expression of mutant HTT protein is highly sensitive to reduced expression of GW182 (TNRC6A) and its two paralogs, a protein family associated with miRNA action. Allele-selective inhibition may involve cooperative binding of multiple protein-RNA complexes to the expanded repeat. These data suggest that allele-selective inhibition proceeds through an RNA interference pathway similar to that used by miRNAs and that discrimination between mutant and wild-type alleles of HTT mRNA is highly sensitive to the pool of AGO2 and GW182 family proteins inside cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.