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

Abstract

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 (CAG ex 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.

FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease

“…Faster somatic expansion rates correlate with earlier age at onset and faster disease progression (Bates et al, 2015;Rawlins et al, 2016;Flower et al, 2019;Swami et al, 2009;Wright et al, 2019). The expanded CAG repeat may be pathogenic through several mechanisms, including at the protein level through translation into a longer, more toxic polyglutamine tract; at the RNA level through the incomplete splicing of HTT (Neueder et al, 2017;Sathasivam et al, 2013), RAN translation, or RNA secondary structure (Bañ ez-Coronel et al, 2015;Schilling et al, 2016) ; and at the DNA level through an effect on transcription and DNA repair activity (Wright et al, 2020). Targeting repeat expansion, the most proximal pathogenic event, represents a prime therapeutic opportunity in HD and potentially other trinucleotide disorders (Tabrizi et al, 2020).…”

Huntingtin and Its Role in Mechanisms of RNA-Mediated Toxicity

“…Not only do the CAG-repeat lengths influence hairpin stability but also specific repeat-flanking regions at the stem can stabilize the hairpin structure by serving as a G–C clamp [ 32 ]. These aberrantly formed mutant CAG-repeat hairpin motifs interfere with the normal cellular functions by aberrantly recruiting RNA-binding proteins [ 32 , 33 ]. The sequestration of these proteins to the hairpin hinders the function of several pathways they are a part of, leading to the breakdown of the cellular system.…”

Role and Perspective of Molecular Simulation-Based Investigation of RNA–Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding

“…Since normal HTT mRNAs do not feature hairpin structures, a relevant role for the RNA structure in inducing a toxic effect is very likely [ 34 ]. The expanded CAG repeat hairpin structure is able to bind to and interact with several proteins in a length-dependent manner, thereby contributing to HD pathogenicity ( Figure 1 ) [ 35 , 36 ].…”