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

Maria Jimenez-Sanchez; Wun Lam; Michael Hannus; Birte Sönnichsen; Sara Imarisio; Angeleen Fleming; Alessia Tarditi; Fiona Menzies; Teresa Ed Dami; Catherine Xu; Eduardo Gonzalez-Couto; Giulia Lazzeroni; Freddy Heitz; Daniela Diamanti; Luisa Massai; Venkata P Satagopam; Guido Marconi; Chiara Caramelli; Arianna Nencini; Matteo Andreini; Gian Luca Sardone; Nicola P Caradonna; Valentina Porcari; Carla Scali; Reinhard Schneider; Giuseppe Pollio; Cahir J O'Kane; Andrea Caricasole; David C Rubinsztein

doi:10.1038/nchembio.1790

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. Epub 2015 Apr 6.

Authors

Maria Jimenez-Sanchez¹, Wun Lam^{1

2}, Michael Hannus^#³, Birte Sönnichsen^#³, Sara Imarisio^#^{1

2}, Angeleen Fleming^#^{1

4}, Alessia Tarditi⁵, Fiona Menzies¹, Teresa Ed Dami^{1

4

6}, Catherine Xu^{1

4}, Eduardo Gonzalez-Couto⁵, Giulia Lazzeroni⁵, Freddy Heitz⁵, Daniela Diamanti⁵, Luisa Massai⁵, Venkata P Satagopam^{7

8}, Guido Marconi⁵, Chiara Caramelli⁵, Arianna Nencini⁵, Matteo Andreini⁵, Gian Luca Sardone⁵, Nicola P Caradonna⁵, Valentina Porcari⁵, Carla Scali⁵, Reinhard Schneider^{7

8}, Giuseppe Pollio⁵, Cahir J O'Kane², Andrea Caricasole⁵, David C Rubinsztein¹

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminoacyltransferases / antagonists & inhibitors
Aminoacyltransferases / drug effects*
Aminoacyltransferases / genetics*
Animals
Cells, Cultured
Computational Biology
Drosophila
Drug Evaluation, Preclinical
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Green Fluorescent Proteins / metabolism
Humans
Huntingtin Protein
Huntington Disease / drug therapy*
Huntington Disease / genetics*
Mice
Mice, Inbred C57BL
Mutation / genetics
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neurons / drug effects
Neurons / metabolism
RNA, Small Interfering*
Zebrafish
alpha-Crystallin B Chain / metabolism

Substances

Enzyme Inhibitors
HTT protein, human
Huntingtin Protein
Nerve Tissue Proteins
RNA, Small Interfering
alpha-Crystallin B Chain
enhanced green fluorescent protein
Green Fluorescent Proteins
Aminoacyltransferases
glutaminyl-peptide cyclotransferase

Associated data

PubChem-Substance/249494159
PubChem-Substance/249494160
PubChem-Substance/249494161
PubChem-Substance/249494162
PubChem-Substance/249494163
PubChem-Substance/249494164
PubChem-Substance/249494165
PubChem-Substance/249494166
PubChem-Substance/249494167
PubChem-Substance/249494168

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding