Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds
Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds
复制标题
HTT-LC3 连接化合物对突变 HTT 蛋白的等位基因选择性降低。
DOI：
10.1038/s41586-019-1722-1
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发表时间：
2019-11-07
期刊：
影响因子：
64.8
通讯作者：
Lu, Boxun
中科院分区：
文献类型：
--
作者：
Li, Zhaoyang;Wang, Cen;Lu, Boxun
突变蛋白质的积累是许多疾病（统称为蛋白质病）的主要原因，降低这些蛋白质的水平可用于治疗这些疾病。我们假设，与自噬体蛋白微管相关蛋白1A/1B轻链3（LC 3）（1）和致病蛋白相互作用的化合物可能靶向后者进行自噬清除。突变型亨廷顿蛋白（mHTT）含有一个扩展的多聚谷氨酰胺（polyQ）道，并导致亨廷顿病，一种无法治愈的神经退行性疾病（2）。在这里，使用基于小分子微阵列的筛选，我们确定了四种与LC 3和mHTT相互作用的化合物，但不与野生型HTT蛋白相互作用。这些化合物中的一些将mHTT靶向自噬体，以等位基因选择性方式降低mHTT水平，并在亨廷顿病的苍蝇和小鼠模型的细胞和体内挽救疾病相关表型。我们进一步表明，这些化合物与扩展的polyQ片段相互作用，可以降低突变型共济失调蛋白-3（ATXN 3）的水平，ATXN 3是另一种具有扩展polyQ片段的致病蛋白（3）。这项研究提出了降低mHTT和潜在的其他致病蛋白与polyQ扩增的候选化合物，证明了使用自噬体拴系化合物降低致病蛋白水平的概念。
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 disorder(2). 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 tract(3). 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.