Abstract

Huntington's disease (HD) is caused by the abnormal expansion of CAG repeats located in the translated region of HTT gene, which gives rise to a large, multifunctional HTT protein containing a long polyglutamine tract. The disease pathogenesis is commonly attributed to the alteration of numerous cellular functions by the mutant protein. The toxic HTT protein, however, derives from a mutant transcript, and mounting evidence suggests that the RNA is also toxic to cells and contributes to HD pathogenesis. During the search for mechanisms of HD pathogenesis triggered directly by mutant RNA, lessons can be learnt from other triplet repeat expansion diseases triggered by mutant transcripts. These diseases include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome, in which expanded CUG repeats and CGG repeats, respectively, are located in non-translated regions of the implicated genes. The mechanisms identified in these triplet repeat expansion diseases include aberrant alternative splicing, the inhibition of nuclear transport and export, the induction of the innate immune response, an altered microRNA biogenesis pathway and an abnormal activation of RNA interference pathway. Possible directions for future investigations of the mechanisms of HD pathogenesis triggered directly by mutant RNA repeats will be discussed.