复旦大学生命科学学院鲁伯埙、丁澦以及复旦大学信息科学与工程学院费义艳等研究人员合作，开发出能够利用细胞自噬作用选择性降低突变亨廷顿（HTT）蛋白的小分子化合物。2019年10月30日，《自然》杂志在线发表了这项研究成果。

研究人员介绍，突变蛋白的积累是许多疾病（统称为蛋白病）的主要原因，降低这些蛋白的水平可用于治疗这些疾病。

研究人员假设与自噬小体蛋白微管相关蛋白1A / 1B轻链3（LC3）和致病蛋白都相互作用的化合物可能针对后者进行自噬清除。突变的亨廷顿蛋白（mHTT）包含延伸的多聚谷氨酰胺（polyQ），并引起亨廷顿氏病，这是一种不可治愈的神经退行性疾病。通过使用基于小分子微阵列的筛选，研究人员确定了四种与LC3和mHTT相互作用但与野生型HTT蛋白不相互作用的化合物。其中一些化合物将mHTT靶向自噬体，以等位基因选择性方式降低mHTT水平，并在亨廷顿舞蹈病的果蝇和小鼠模型中挽救了细胞和体内与疾病相关的表型。

研究人员进一步表明，这些化合物与延伸的polyQ相互作用，并可能降低突变的共济失调蛋白3（ATXN3）的水平，后者是另一种具有延伸polyQ的致病蛋白。这项研究提出了可降低mHTT和可能具有polyQ延伸作用的其他致病蛋白的候选化合物，证明了使用自噬连接蛋白降低致病蛋白水平的概念。

附：英文原文

Title: Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds

Author: Zhaoyang Li, Cen Wang, Ziying Wang, Chenggang Zhu, Jie Li, Tian Sha, Lixiang Ma, Chao Gao, Yi Yang, Yimin Sun, Jian Wang, Xiaoli Sun, Chenqi Lu, Marian Difiglia, Yanai Mei, Chen Ding, Shouqing Luo, Yongjun Dang, Yu Ding, Yiyan Fei, Boxun Lu

Issue&Volume: 2019-10-30

Abstract: 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 Huntingtons 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 Huntingtons 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.

DOI: 10.1038/s41586-019-1722-1

Source:https://www.nature.com/articles/s41586-019-1722-1