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.
Keywords: CAG repeats; RNA binding proteins; RNA toxicity; polyglutamine disorders.
© 2016 International Society of Neuropathology.