Truncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form

Huiming Yang, Su Yang, Liang Jing, Luoxiu Huang, Luxiao Chen, Xianxian Zhao, Weili Yang, Yongcheng Pan, Peng Yin, Zhaohui S Qin, Beisha Tang, Shihua Li () and Xiao-Jiang Li ()
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Huiming Yang: Sun Yat-sen University
Su Yang: Jinan University
Liang Jing: Emory University School of Medicine
Luoxiu Huang: Emory University School of Medicine
Luxiao Chen: Emory University
Xianxian Zhao: Jinan University
Weili Yang: Jinan University
Yongcheng Pan: Emory University School of Medicine
Peng Yin: Jinan University
Zhaohui S Qin: Emory University
Beisha Tang: Xiangya Hospital, Central South University
Shihua Li: Jinan University
Xiao-Jiang Li: Jinan University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16318-1

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