Alterations in mRNA 3′ UTR Isoform Abundance Accompany Gene Expression Changes in Human Huntington’s Disease Brains

The huntingtin gene has two mRNA isoforms that differ in their 3′ UTR length. The relationship of these isoforms with Huntington’s disease is not established. We provide evidence that the abundance of huntingtin 3′ UTR isoforms differs between patient and control neural stem cells, fibroblasts, motor cortex, and cerebellum. Huntingtin 3′ UTR isoforms, including a mid-3′ UTR isoform, have different localizations, half-lives, polyA tail lengths, microRNA sites, and RNA-binding protein sites. Isoform shifts in Huntington’s disease motor cortex are not limited to huntingtin; 11% of alternatively polyadenylated genes change the abundance of their 3′ UTR isoforms. Altered expression of RNA-binding proteins may be associated with aberrant isoform abundance; knockdown of the RNA-binding protein CNOT6 in control fibroblasts leads to huntingtin isoform differences similar to those in disease fibroblasts. These findings demonstrate that mRNA 3′ UTR isoform changes are a feature of molecular pathology in the Huntington’s disease brain. [Display omitted] •The relative abundance of huntingtin 3′ UTR isoforms changes in Huntington’s disease•Huntingtin 3′ UTR isoforms are metabolized differently•Many other genes associated with Huntington’s pathogenesis exhibit isoform changes•Knockdown of the CNOT6 RNA-binding protein recapitulates some isoform alterations Romo et al. show that the abundance of mRNA 3′ UTR isoforms of huntingtin and a subset of other genes changes in Huntington’s disease motor cortex. Genes with isoform alterations occur in pathways implicated in disease pathogenesis. Differential expression of RNA-binding proteins may cause these isoform changes in Huntington’s disease.