Aberrant splicing of mutant huntingtin in Huntington's disease knock-in pigs

• DOI: 10.1016/j.nbd.2023.106291
• Publication Date: 2023-09-15T07:50:15Z
• Authors: Huichun Tong; Tianqi Yang; Li Liu; Caijuan Li; Yize Sun; Qingqing Jia; Yiyang Qin; Laiqiang Chen; Xianxian Zhao; Gongke Zhou; Sen Yan; Xiao-Jiang Li; Shihua Li
• Keywords: Huntingtin Protein; Gene knockin; Polyglutamine tract

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative caused by a CAG repeat expansion in exon1 of the huntingtin gene (HTT). This leads to production N-terminal mutant protein (mHtt) that contains expanded polyglutamine tract, which toxic neurons and causes neurodegeneration. While mHtt can be mediated proteolytic cleavage full-length mHtt, abnormal splicing exon1-intron1 has also been identified brains HD mice patients. However, proportion aberrantly spliced mHTT relation normal exon remains defined. In this study, HTT was examined knock-in (KI) pig model, more closely recapitulates neuropathology seen patient than mouse models. The study revealed aberrant present pigs, but it expressed at much lower level normally products. These findings suggest careful consideration needed when assessing contribution pathogenesis, further rigorous investigation required.