Reference : siRNA screen identifies QPCT as a druggable target for Huntington's disease.
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
siRNA screen identifies QPCT as a druggable target for Huntington's disease.
Jimenez-Sanchez, Maria [> >]
Lam, Wun [> >]
Hannus, Michael [> >]
Sonnichsen, Birte [> >]
Imarisio, Sara [> >]
Fleming, Angeleen [> >]
Tarditi, Alessia [> >]
Menzies, Fiona [> >]
Ed Dami, Teresa [> >]
Xu, Catherine [> >]
Gonzalez-Couto, Eduardo [> >]
Lazzeroni, Giulia [> >]
Heitz, Freddy [> >]
Diamanti, Daniela [> >]
Massai, Luisa [> >]
Satagopam, Venkata mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Marconi, Guido [> >]
Caramelli, Chiara [> >]
Nencini, Arianna [> >]
Andreini, Matteo [> >]
Sardone, Gian Luca [> >]
Caradonna, Nicola P. [> >]
Porcari, Valentina [> >]
Scali, Carla [> >]
Schneider, Reinhard mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Pollio, Giuseppe [> >]
O'Kane, Cahir J. [> >]
Caricasole, Andrea [> >]
Rubinsztein, David C. [> >]
Nature chemical biology
Yes (verified by ORBilu)
[en] 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 alphaB-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.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
FP7: 37472 - TAMAHUD - Identification of early disease markers, novel pharmacologically tractable targets and small molecule phenotypic modulators in Huntington's Disease

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