siRNA screen identifies QPCT as a druggable target for Huntington's disease
Open Access
- 6 April 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 11 (5), 347-354
- https://doi.org/10.1038/nchembio.1790
Abstract
An siRNA screen for genes that suppress mutant huntingtin toxicity in both mammalian cells and Drosophila identifies glutaminyl cyclase (QPCT). Newly generated small-molecule inhibitors further identify QPCT as a druggable target for Huntington′s disease. 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.Keywords
This publication has 59 references indexed in Scilit:
- Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington diseaseProceedings of the National Academy of Sciences of the United States of America, 2013
- Molecular chaperones in protein folding and proteostasisNature, 2011
- Structures of Human Golgi-resident Glutaminyl Cyclase and Its Complexes with Inhibitors Reveal a Large Loop Movement upon Inhibitor BindingJournal of Biological Chemistry, 2011
- Matrix Metalloproteinases Are Modifiers of Huntingtin Proteolysis and Toxicity in Huntington's DiseaseNeuron, 2010
- Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregationProceedings of the National Academy of Sciences of the United States of America, 2010
- The Interaction of αB-Crystallin with Mature α-Synuclein Amyloid Fibrils Inhibits Their ElongationBiophysical Journal, 2010
- Novel targets for Huntington's disease in an mTOR-independent autophagy pathwayNature Chemical Biology, 2008
- A genome-wide transgenic RNAi library for conditional gene inactivation in DrosophilaNature, 2007
- Improved protein–ligand docking using GOLDProteins-Structure Function and Bioinformatics, 2003
- Stages of embryonic development of the zebrafishDevelopmental Dynamics, 1995