RNA toxicity in polyglutamine disorders: concepts, models, and progress of research

In Huntington's disease and other polyglutamine (polyQ) disorders, mutant proteins containing a long polyQ stretch are well documented as the trigger of numerous aberrant cellular processes that primarily lead to degeneration and, ultimately, the death of neuronal cells. However, mutant transcripts containing expanded CAG repeats may also be toxic and contribute to cellular dysfunction. The exact nature and importance of RNA toxicity in polyQ diseases are only beginning to be recognized, and the first insights have mainly resulted from studies using simple model systems. In this review, we briefly present the basic mechanisms of protein toxicity in polyQ disorders and RNA toxicity in myotonic dystrophy type 1 and discuss recent results suggesting that the pathogenesis of polyQ diseases may also be mediated by mutant transcripts. This review is focused on the experimental systems used thus far to demonstrate RNA toxicity in polyQ disorders and the design of new systems that will be more relevant to the human disease situation and capable of separating RNA toxicity from protein toxicity.