Pathogenic TDP‐43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock‐in mice

Abstract Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length‐dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP‐43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP‐43 is mislocalized in the cytoplasm. By investigating HD knock‐in mice, we explore whether the pathogenic TDP‐43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP‐43 without nuclear localization signal. We found that the cytoplasmic TDP‐43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP‐43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre‐mRNA, promotes the transport of exon1‐intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP‐43 contributes to HD pathogenesis via its binding to and transport of nuclear un‐spliced mRNA to the ribosome for the generation of a toxic protein product.