Abstract
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.
Highlights
CAG repeat mRNAs fold into hairpin structures, which increase in size and stability with increasing repeat length
We have shown recently that HTT mRNAs carrying expanded CAG repeats bind to a protein complex containing the MID1 protein, the catalytic subunit of protein phosphatase 2A (PP2Ac) and 40S ribosomal S6 kinase (S6K), a target of mTOR kinase and PP2A.70
The studies highlighted above demonstrate that CAG repeat expansions in mRNAs can contribute to neurotoxicity
Summary
Are RNA-mediated mechanisms specific to distinct mRNAs or are they common to all CXG repeats?. The case for direct CAG repeat RNA-mediated toxicity is further bolstered by a second group of CAG repeat diseases, wherein the expanded repeat regions are located in the UTR. The expansion of a CAG repeat in the 50 UTR is linked to disease development in SCA12 (OMIM 604 326). These observations suggest that toxic mRNA species with expanded CAG repeats contribute significantly to disease development in the absence of polyQ proteins. We focus on the various pathogenic modalities of mRNAs with expanded CAG repeats. These include the sequestration of several proteins and transcription factors. We discuss the effect of expanded CAG repeats on subcellular localization, the transcriptional regulation of CAG mRNA and translation misregulation
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