ArticlePLoS genetics2012
A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers, 1 of them a synthesis that pooled it.
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Who cites it
116 citing papers in PubMed, 1 synthesis or guideline pooled it, 186 citations in OpenAlex.
- The Role of MicroRNA in Diagnosis of Huntington's Disease: A Systematic Review.Molecular neurobiology · 2026Pooled it
- Clinical-Grade Human Induced Pluripotent Stem Cell-Derived Neural Precursor Cells Restore Motor Function and Preserve Striatal Integrity in a Quinolinic Acid-Lesioned Rat Model of Huntington's Disease.Cell proliferation · 2026Article
- Developing a pan cancer therapy based on DISE-inducing short RNAs.Molecular therapy. Nucleic acids · 2026Article
- Overexpression of the Dicer family genes influences lifespan and stress resistance in a tissue-, sex-, and stressor-specific manner in Drosophila melanogaster.Biogerontology · 2025Article
- Advances in Huntington's Disease Biomarkers: A 10-Year Bibliometric Analysis and a Comprehensive Review.Biology · 2025Review
- RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington's disease models.Molecular neurodegeneration · 2025Article
- Anti-gene oligonucleotide clamps invade dsDNA and downregulateMolecular therapy. Nucleic acids · 2024Article
- Nuclear pore dysfunction and disease: a complex opportunity.Nucleus (Austin, Tex.) · 2024Review
- UBL3 Interacts with PolyQ-Expanded Huntingtin Fragments and Modifies Their Intracellular Sorting.Neurology international · 2024Article
- Age- and disease-related autophagy impairment in Huntington disease: New insights from direct neuronal reprogramming.Aging cell · 2024Review
- Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat.Nature communications · 2024Article
- Non-fibril form but not fibril form of human islet amyloid polypeptide 8-20 changes brain functions in mice.PloS one · 2024Article
- Review
- Functional Characterisation of the Circular RNA,Cells · 2023Article
- Non-coding RNAs in human health and disease: potential function as biomarkers and therapeutic targets.Functional & integrative genomics · 2023Review
- A promising nucleic acid therapy drug: DNAzymes and its delivery system.Frontiers in molecular biosciences · 2023Review
- The length of uninterrupted CAG repeats in stem regions of repeat disease associated hairpins determines the amount of short CAG oligonucleotides that are toxic to cells through RNA interference.Cell death & disease · 2022Article
- Huntingtin and Other Neurodegeneration-Associated Proteins in the Development of Intracellular Pathologies: Potential Target Search for Therapeutic Intervention.International journal of molecular sciences · 2022Review
- Development of Fluorescent Turn-On Probes for CAG-RNA Repeats.Biosensors · 2022Article
- A peptide inhibitor that rescues polyglutamine-induced synaptic defects and cell death through suppressing RNA and protein toxicities.Molecular therapy. Nucleic acids · 2022Article
56 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.
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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.