siRNA screen identifies QPCT as a druggable target for Huntington's disease.
siRNA screen identifies QPCT as a druggable target for Huntington's disease.
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DOI：
10.1038/nchembio.1790
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发表时间：
2015-05
影响因子：
14.8
通讯作者：
Rubinsztein DC
中科院分区：
文献类型：
--
作者：
Jimenez-Sanchez M;Lam W;Hannus M;Sönnichsen B;Imarisio S;Fleming A;Tarditi A;Menzies F;Dami TE;Xu C;Gonzalez-Couto E;Lazzeroni G;Heitz F;Diamanti D;Massai L;Satagopam VP;Marconi G;Caramelli C;Nencini A;Andreini M;Sardone GL;Caradonna NP;Porcari V;Scali C;Schneider R;Pollio G;O'Kane CJ;Caricasole A;Rubinsztein DC
亨廷顿病(HD)是一种目前无法治愈的神经退行性疾病，由亨廷顿蛋白(HTT)中异常扩张的聚谷氨酰胺束引起。我们通过在人类培养细胞中进行大规模的“可药物基因组”siRNA筛选，然后在果蝇中进行HIT验证，确定了突变HTT毒性的新修饰物。我们重点研究了谷氨酰环酶(QPCT)，它在细胞siRNA筛选中对突变的HTT诱导的毒性和聚集有最强的作用，也拯救了果蝇的这些表型。我们发现，抑制QPCT诱导了分子伴侣αB-晶状体蛋白的水平，并减少了不同蛋白质的聚集。我们用电子计算机方法合成了新的QPCT抑制剂，随后进行了体外筛选，挽救了细胞、果蝇和斑马鱼HD模型中与HD相关的表型。我们的数据揭示了一个新的HD可药物靶点影响突变的Huntingtin聚集，并为从可药物基因组筛选到药物开发的发现管道提供了原理证明。
Huntington’s disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified novel 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 which also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone alpha B-crystallin and reduced the aggregation of diverse proteins. We generated novel QPCT inhibitors using in silico methods followed by in vitro screens, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a novel HD druggable target affecting mutant huntingtin aggregation, and provide proof-of-principle for a discovery pipeline from druggable genome screen to drug development.