Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form
Huiming Yang, Su Yang, Jing Liang, Luoxiu Huang, Luxiao Chen, Xianxian Zhao, Weili Yang, Yongcheng Pan, Peng Yin, Zhaohui Qin, Beisha Tang, Shihua Li, Xiao‐Jiang Li
Abstract
Polyglutamine expansion in proteins can cause selective neurodegeneration, although the mechanisms are not fully understood. In Huntington's disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Here, using CRISPR/Cas9 to truncate full-length mutant HTT in HD140Q knock-in (KI) mice, we show that exon 1 HTT is stably present in the brain, regardless of truncation sites in full-length HTT. This N-terminal HTT leads to similar HD-like phenotypes and age-dependent HTT accumulation in the striatum in different KI mice. We find that exon 1 HTT is constantly generated but its selective accumulation in the striatum is associated with the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function contributes to the selective neuropathology in HD, and highlight the therapeutic potential in blocking generation of exon 1 HTT.