Mechanisms of RNA-induced toxicity in CAG repeat disorders.

Several inherited neurodegenerative disorders are caused by CAG trinucleotide repeat expansions, which can be located either in the coding region or in the untranslated region (UTR) of the respective genes. Polyglutamine diseases (polyQ diseases) are caused by an expansion of a stretch of CAG repeats within the coding region, translating into a polyQ tract. The polyQ tract expansions result in conformational changes, eventually leading to aggregate formation. It is widely believed that the aggregation of polyQ proteins is linked with disease development. In addition, in the last couple of years, it has been shown that RNA-mediated mechanisms also have a profound role in neurotoxicity in both polyQ diseases and diseases caused by elongated CAG repeat motifs in their UTRs. Here, we review the different molecular mechanisms assigned to mRNAs with expanded CAG repeats. One aspect is the mRNA folding of CAG repeats. Furthermore, pathogenic mechanisms assigned to CAG repeat mRNAs are discussed. First, we discuss mechanisms that involve the sequestration of the diverse proteins to the expanded CAG repeat mRNA molecules. As a result of this, several cellular mechanisms are aberrantly regulated. These include the sequestration of MBNL1, leading to misregulated splicing; sequestration of nucleolin, leading to reduced cellular rRNA; and sequestration of proteins of the siRNA machinery, resulting in the production of short silencing RNAs that affect gene expression. Second, we discuss the effect of expanded CAG repeats on the subcellular localization, transcription and translation of the CAG repeat mRNA itself. Here we focus on the MID1 protein complex that triggers an increased translation of expanded CAG repeat mRNAs and a mechanism called repeat-associated non-ATG translation, which leads to proteins aberrantly translated from CAG repeat mRNAs. In addition, therapeutic approaches for CAG repeat disorders are discussed. Together, all the findings summarized here show that mutant mRNA has a fundamental role in the pathogenesis of CAG repeat diseases.