Mechanisms of RNA‐Induced Toxicity in Diseases Characterised by CAG Repeat Expansions


Expansion disorders involving the trinucleotide CAG (cytosine–adenine–guanine) cause diverse progressive neurodegenerative phenotypes. The expanded CAG repeat can be located in the coding region, where it is translated into extended polyglutamine stretches or in the untranslated region (UTR) of the respective gene. The polyglutamine diseases are characterised by aggregate formation of polyglutamine protein, a process that is widely believed to play a role in disease development. In addition, there is emerging evidence showing that RNA (ribonucleic acid)‐mediated mechanisms also contribute to neurotoxicity in both polyglutamine diseases and diseases caused by elongated CAG repeat motifs in the UTR. Structurally, RNA with an expanded CAG repeat differs from normal RNA with a physiological CAG repeat stretch: expanded CAG repeat RNAs (CAGex RNAs) fold into hairpin structures that increase in size and stability with increasing CAG repeat numbers. This article discusses how RNA molecules with expanded CAG repeats can execute abnormal functions that contribute to disease development.

Key Concepts

  • Several neurodegenerative diseases are caused by CAG trinucleotide repeat expansions.
  • Pathologically expanded CAG repeat mRNAs fold into hairpin structures, which bind to and sequester diverse proteins.
  • RNA‐mediated mechanisms contribute to neurotoxicity.
  • RNA‐mediated neurotoxic functions depend on the subcellular localisation of the RNA, including cytosolic, nuclear and nucleolar mechanisms.
  • Targeting pathologically expanded CAG repeat mRNAs represents a promising therapeutic approach for treating CAG trinucleotide repeat expansion disorders.

Keywords: neurodegeneration; polyglutamine diseases; CAG repeats; RNA–protein interactions; RNA‐mediated toxicity

Figure 1. CAG repeat RNAs fold into hairpin structures. (a) Schematic showing the hairpin formed by CAG repeat mRNA, consisting of the base, the stem and the loop. The stem consists of G–C and C–G pairs, whereas a wobble is built at the A–A mismatch. (b) Schematic showing how CAG repeat mRNA can fold into slipped hairpins. (c) Schematic showing that normal and mutant CAG repeat RNAs differ in the length of the stem of the CAG hairpin structure. (d) Schematic showing how the flanking regions influence CAG repeat hairpin formation.
Figure 2. Nuclear mechanisms leading to CAGex RNA‐mediated pathogenesis. (a) Schematic visualisation of normal nuclear functions: transcription, splicing and nuclear export of mRNA, as well as rRNA transcription within the nucleolus. (b) Schematic representation of dysfunction in a CAGex RNA expressing nucleus. Pathogenic mechanisms include misregulated transcription and splicing, nuclear retention of CAGex RNA, as well as reduced rRNA transcription inside the nucleolus.
Figure 3. Cytosolic mechanisms leading to CAGex RNA‐mediated pathogenesis. (a) Schematic showing normal translation in a healthy cell. (b) Schematic showing dysfunction of cytosolic CAGex RNA. CAGex RNA gets cleaved by DICER into sCAGs, which silence CTG‐containing transcripts. CAGex RNA serves as a template for polyglutamine (polyQ), polyserine (polyS) and polyalanine (polyA) proteins.


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Further Reading

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Schilling, Judith, Griesche, Nadine, and Krauß, Sybille(Jan 2016) Mechanisms of RNA‐Induced Toxicity in Diseases Characterised by CAG Repeat Expansions. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026464]