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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\u2010dependent aberrant splicing of exon1 <jats:italic>HTT<\/jats:italic> results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP\u201043 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP\u201043 is mislocalized in the cytoplasm. By investigating HD knock\u2010in mice, we explore whether the pathogenic TDP\u201043 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP\u201043 without nuclear localization signal. We found that the cytoplasmic TDP\u201043 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP\u201043, via its binding to the intron1 sequence (GU\/UG)n of the mouse <jats:italic>Htt<\/jats:italic> pre\u2010mRNA, promotes the transport of exon1\u2010intron1 <jats:italic>Htt<\/jats:italic> onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP\u201043 contributes to HD pathogenesis via its binding to and transport of nuclear un\u2010spliced mRNA to the ribosome for the generation of a toxic protein product.<\/jats:p>","DOI":"10.1111\/acel.14325","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T10:53:45Z","timestamp":1724669625000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pathogenic <scp>TDP<\/scp>\u201043 accelerates the generation of toxic exon1 <scp>HTT<\/scp> in Huntington's disease knock\u2010in mice"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9475-5003","authenticated-orcid":false,"given":"Dazhang","family":"Bai","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Key Laboratory of non\u2010human Primate Research, Guangdong\u2010Hongkong\u2010Macau 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