亨廷顿蛋白
突变体
亨廷顿蛋白
聚谷氨酰胺束
自噬
细胞生物学
突变蛋白
化学
遗传学
蛋白质聚集
表型
生物
基因
细胞凋亡
作者
Zhaoyang Li,Cen Wang,Ziying Wang,Chenggang Zhu,Jie Li,Sha Tian,Lixiang Ma,Chao Gao,Yi Yang,Yi‐Min Sun,Jian Wang,Xiaoli Sun,Chenqi Lu,Marian DiFiglia,Yan‐Ai Mei,Ding Chen,Shouqing Luo,Yongjun Dang,Yu Ding,Yiyan Fei,Boxun Lu
出处
期刊:Nature
[Springer Nature]
日期:2019-10-30
卷期号:575 (7781): 203-209
被引量:308
标识
DOI:10.1038/s41586-019-1722-1
摘要
Accumulation of mutant proteins is a major cause of many diseases (collectively called proteopathies), and lowering the level of these proteins can be useful for treatment of these diseases. We hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain 3 (LC3)1 and the disease-causing protein may target the latter for autophagic clearance. Mutant huntingtin protein (mHTT) contains an expanded polyglutamine (polyQ) tract and causes Huntington’s disease, an incurable neurodegenerative disorder2. Here, using small-molecule-microarray-based screening, we identified four compounds that interact with both LC3 and mHTT, but not with the wild-type HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington’s disease. We further show that these compounds interact with the expanded polyQ stretch and could lower the level of mutant ataxin-3 (ATXN3), another disease-causing protein with an expanded polyQ tract3. This study presents candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyQ expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds. Compounds that interact with mutant huntingtin and an autophagosomal protein are able to reduce cellular levels of mutant huntingtin by targeting it for autophagic degradation, demonstrating an approach that may have potential for treating proteopathies.
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