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Huntington’s disease (HD) is caused by a CAG repeat expansion in the huntingtin ( HTT ) gene. Recent evidence suggests that HD is a consequence of multimodal, non-mutually exclusive mechanisms of pathogenesis that involve both HTT protein- and  HTT  RNA-triggered mechanisms. Here we provide further evidence for the role of expanded  HTT (expHTT)  RNA in HD by demonstrating that a fragment of  expHTT  is cytotoxic in the absence of any translation and that the extent of cytotoxicity is similar to the cytotoxicity of an expHTT protein fragment encoded by a transcript of similar length and with a similar repeat size. In addition, full-length (FL)  expHTT  is retained in the nucleus. Overexpression of the splicing factor muscleblind-like 1 (MBNL1) increases nuclear retention of  expHTT  and decreases the expression of expHTT protein in the cytosol. The splicing and nuclear export factor U2AF65 has the opposite effect, decreasing exp HTT  nuclear retention and increasing expression of expHTT protein. This suggests that MBNL1 and U2AF65 play a role in nuclear export of  expHTT  RNA.

Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65