2. Academic Validation
  3. siRNA screen identifies QPCT as a druggable target for Huntington's disease

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

  • Nat Chem Biol. 2015 May;11(5):347-354. doi: 10.1038/nchembio.1790.
Maria Jimenez-Sanchez 1,  Wun Lam 1 2,  Michael Hannus  # 3,  Birte Sönnichsen  # 3,  Sara Imarisio  # 1 2,  Angeleen Fleming  # 1 4,  Alessia Tarditi 5,  Fiona Menzies 1,  Teresa Ed Dami 1 4 6,  Catherine Xu 1 4,  Eduardo Gonzalez-Couto 5,  Giulia Lazzeroni 5,  Freddy Heitz 5,  Daniela Diamanti 5,  Luisa Massai 5,  Venkata P Satagopam 7 8,  Guido Marconi 5,  Chiara Caramelli 5,  Arianna Nencini 5,  Matteo Andreini 5,  Gian Luca Sardone 5,  Nicola P Caradonna 5,  Valentina Porcari 5,  Carla Scali 5,  Reinhard Schneider 7 8,  Giuseppe Pollio 5,  Cahir J O'Kane 2,  Andrea Caricasole 5,  David C Rubinsztein 1
Affiliations

Affiliations

  • 1 Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
  • 2 Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
  • 3 Cenix BioScience GmbH, Tatzberg 47, 01307 Dresden, Germany.
  • 4 Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK, CB2 3EG.
  • 5 Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
  • 6 Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
  • 7 Structural and Computational Biology, EMBL, Meyerhofstr.1, 69117, Heidelberg, Germany.
  • 8 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Campus Belval, House of Biomedicine, 7 avenue des Hauts-Fourneaux, L-4362 Esch-sur-Alzette, Luxembourg.
  • # Contributed equally.
PMID: 25848931 DOI: 10.1038/nchembio.1790
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.

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