Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
Nat Chem Biol. 2015 May;11(5):347-354. doi: 10.1038/nchembio.1790. Epub 2015 Apr 6.
Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development.
亨廷顿病（HD）是一种由亨廷顿蛋白（HTT）中异常扩展的多聚谷氨酰胺片段引起的不可治愈的神经退行性疾病。我们通过在人类培养细胞中进行大规模的“可用药基因组”siRNA 筛选，然后在果蝇中进行命中验证，确定了新的突变 HTT 毒性调节剂。我们专注于谷氨酰胺环化酶（QPCT），它在基于细胞的 siRNA 筛选中对突变 HTT 诱导的毒性和聚集具有最强的影响之一，并且在果蝇中也挽救了这些表型。我们发现 QPCT 抑制诱导了分子伴侣αB-晶状体蛋白的水平，并减少了多种蛋白质的聚集。我们使用计算机方法生成了新的 QPCT 抑制剂，然后进行了体外筛选，在细胞、果蝇和斑马鱼 HD 模型中挽救了与 HD 相关的表型。我们的数据揭示了一个新的可治疗 HD 的靶点，该靶点影响突变 HTT 的聚集，并为从可用药基因组筛选到药物开发的发现途径提供了原理证明。
