title: 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.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Jimenez-Sanchez
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.|Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Wun
authors.initials: W
authors.lastname: Lam
authors.affiliation: Cenix BioScience GmbH, Tatzberg 47, 01307 Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hannus
authors.affiliation: Cenix BioScience GmbH, Tatzberg 47, 01307 Dresden, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Sönnichsen
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.|Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK, CB2 3EG.
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Tarditi
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Menzies
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK, CB2 3EG.|Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Teresa Ed
authors.initials: TE
authors.lastname: Dami
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK, CB2 3EG.
authors.forename: Catherine
authors.initials: C
authors.lastname: Xu
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gonzalez-Couto
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Lazzeroni
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Freddy
authors.initials: F
authors.lastname: Heitz
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Diamanti
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Massai
authors.affiliation: Structural and Computational Biology, EMBL, Meyerhofstr.1, 69117, Heidelberg, Germany.|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.
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Satagopam
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Marconi
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Caramelli
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Nencini
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Andreini
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Sardone
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Nicola P
authors.initials: NP
authors.lastname: Caradonna
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Porcari
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Scali
authors.affiliation: Structural and Computational Biology, EMBL, Meyerhofstr.1, 69117, Heidelberg, Germany.|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.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pollio
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.affiliation: Siena Biotech. Strada del Petriccio e Belriguardo, 35 53100 Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D004330:Drosophila; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering; D015027:Zebrafish; D038203:alpha-Crystallin B Chain / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D038203:alpha-Crystallin B Chain; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase
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