Related Experiment Video
Updated: Mar 16, 2026
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
RNA toxicity induced by expanded CAG repeats in Huntington's disease
Eulàlia Martí1,2,3,4
1Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Spain.
Insights
Huntington's disease (HD) involves toxic RNA gain-of-function from expanded CAG repeats in the Huntingtin (HTT) gene. These RNA mechanisms, including altered gene expression and small RNAs, contribute to HD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is an inherited polyglutamine disease.
- It's caused by expanded CAG repeats in the Huntingtin (HTT) gene, leading to mutant protein aggregation.
- Recent research highlights novel pathogenic pathways involving RNA toxic gain-of-function.
Purpose of the Study:
- To review evidence and mechanisms of RNA toxicity in CAG repeat expansions, focusing on HD.
- To explore how expanded CAG repeats in HTT mRNA induce toxicity.
- To discuss implications for HD and other CAG repeat diseases.
Main Methods:
- Review of existing literature on RNA toxicity in CAG repeat expansions.
- Analysis of mechanisms including abnormal transcript localization, protein sequestration, and small RNA activity.
- Focus on Huntington's disease models.
Main Results:
- Expanded CAG repeats in HTT mRNA cause toxicity via gene expression perturbations.
- Mechanisms include abnormal subcellular localization of transcripts.
- Protein sequestration by repeats disrupts splicing and gene expression.
- Aberrant small CAG-repeat RNAs (sCAGs) contribute to altered gene silencing.
Conclusions:
- RNA toxic gain-of-function is a key pathogenic pathway in Huntington's disease.
- These RNA-mediated mechanisms offer new insights into HD and related disorders.
- Further research is needed to fully understand the contribution of these pathways to HD progression.
Abstract:
Huntington's disease (HD) belongs to the group of inherited polyglutamine (PolyQ) diseases caused by an expanded CAG repeat in the coding region of the Huntingtin (HTT) gene that results in an elongated polyQ stretch. Abnormal function and aggregation of the mutant protein has been typically delineated as the main molecular cause underlying disease development. However, the most recent advances have revealed novel pathogenic pathways directly dependent on an RNA toxic gain-of-function. Expanded CAG repeats within exon 1 of the HTT mRNA induce toxicity through mechanisms involving, at least in part, gene expression perturbations. This has important implications not only for basic and translational research in HD, but also for other types of diseases carrying the expanded CAG in other genes, which likely share pathogenic aspects. Here I will review the evidence and mechanisms underlying RNA toxicity in CAG repeat expansions, with particular focus on HD. These comprise abnormal subcellular localization of the transcripts containing the expanded CAG repeats; sequestration of several types of proteins by the expanded CAG repeat which results in defects of alternative splicing events and gene expression; and aberrant biogenesis and detrimental activity of small CAG repeated RNAs (sCAG) that produce altered gene silencing. Although these altered pathways have been detected in HD models, their contribution to disease development and progress requires further study.
