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

• Type of Material: Article
• Authors: Huiming Yang, Sun Yat Sen University; Su Yang, Jinan University; Liang Jing, Emory University; Luoxiu Huang, Emory University; Luxiao Chen, Emory University; Xianxian Zhao, Jinan University; Weili Yang, Jinan University; Yongcheng Pan, Sun Yat Sen University; Peng Yin, Jinan University; Xiao-Jiang Li, Emory University; Zhaohui Qin, Emory University
• Language: English
• Date: 2020-05-22
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020, corrected publication 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-16318-1
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 2582
• End Page: 2582
• Grant/Funding Information: This work was supported by the NIH of the United States of America (NS036232, NS101701, NS095279, and NS095181), The National Key Research and Development Program of China Stem Cell and Translational Research (2017YFA0105102), National Natural Science Foundation of China (81830032; 31872779), and Key Field Research and Development Program of Guangdong province (2018B0300337001).
• Keywords: Proteins; Mouse model; Neuronal intranuclear inclusions; Multidisciplinary Sciences; Disease; Accumulation; Science & Technology - Other Topics; Proteolysis; Early motor; N-terminal fragments; Abnormalities; Science & Technology
• Research Categories: Biology, Biostatistics; Biology, Genetics; Biology, Bioinformatics; Health Sciences, Public Health; Biology, Neuroscience

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.