siRNA screen identifies QPCT as a druggable target for Huntington’s disease

Abstract:

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.