Details

Autor(en) / Beteiligte

• Yang, Huiming
• Yang, Su
• Jing, Liang
• Huang, Luoxiu
• Chen, Luxiao
• Zhao, Xianxian
• Yang, Weili
• Pan, Yongcheng
• Yin, Peng
• Qin, Zhaohui S
• Tang, Beisha
• Li, Shihua
• Li, Xiao-Jiang

Titel

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

Ist Teil von

• Nature communications, 2020-05, Vol.11 (1), p.2582-15, Article 2582

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.