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

Nature Chemical Biology volume 11, pages 347–354 (2015)Cite this article

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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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Figure 1: Downregulation of QPCT in flies rescues HD toxicity.
Figure 2: QPCT modulates HTT toxicity and aggregation in mammalian cell lines and primary neurons.
Figure 3: Design of QPCT inhibitors that reduce mutant HTT aggregation.
Figure 4: QPCT inhibition induces alpha B-crystallin levels.
Figure 5: Pharmacologic inhibition of QPCT in fly.
Figure 6: Pharmacologic inhibition of QPCT in zebrafish.

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Acknowledgements

We are grateful for funding from the UK Medical Research Council (COEN grant MR/J006904/1 to D.C.R. and C.J.O.'K.), the Wellcome Trust (Principal Fellowship 095317/Z/11/Z, to D.C.R., and strategic award 100140), the National Institute of Health Research Biomedical Research Unit in Dementia at Addenbrooke's Hospital, the TAMAHUD project (European Community FP6 grant no. 03472 under the Thematic Call LSH-2005-2.1.3-8 “Early markers and new targets for neurodegenerative diseases”) and the NEUROMICS project (European Community Seventh Framework Programme under grant agreement no. 2012-305121). We thank J.L. Marsh, N. Perrimon and the Vienna Drosophila RNAi Center for fly stocks; M. Renna and S. Luo for helpful comments; M. Lichtenberg for help with flow cytometry assays; F. Siddiqi and M. Garcia-Arencibia for help with primary cultures; W. Fecke for advice and assistance; and S. Gotta for help in high-resolution MS analysis of compounds.

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Author notes

  1. Alessia Tarditi, Teresa Ed Dami, Eduardo Gonzalez-Couto, Freddy Heitz, Guido Marconi, Chiara Caramelli, Matteo Andreini & Andrea Caricasole

    Present address: Present addresses: TPV GmbH, München, Germany (A.T.); Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy (T.E.D.); PerkinElmer Informatics, Madrid, Spain (E.G.-C.); GenKyoTex S.A., Geneva, Switzerland (F.H.); Autifony S.r.l., Verona, Italy (G.M.); Novartis Vaccines and Diagnostics, Rosia, Italy (C.C.); Department of Neuroscience, IRBM, Pomezia, Rome, Italy (M.A. and A.C.).,

  2. Michael Hannus, Birte Sönnichsen, Sara Imarisio and Angeleen Fleming: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK

    Maria Jimenez-Sanchez, Wun Lam, Sara Imarisio, Angeleen Fleming, Fiona Menzies, Teresa Ed Dami, Catherine Xu & David C Rubinsztein

  2. Department of Genetics, University of Cambridge, Cambridge, UK

    Wun Lam, Sara Imarisio & Cahir J O'Kane

  3. Cenix BioScience GmbH, Dresden, Germany

    Michael Hannus & Birte Sönnichsen

  4. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

    Angeleen Fleming, Teresa Ed Dami & Catherine Xu

  5. Siena Biotech, Siena, Italy

    Alessia Tarditi, Eduardo Gonzalez-Couto, Giulia Lazzeroni, Freddy Heitz, Daniela Diamanti, Luisa Massai, Guido Marconi, Chiara Caramelli, Arianna Nencini, Matteo Andreini, Gian Luca Sardone, Nicola P Caradonna, Valentina Porcari, Carla Scali, Giuseppe Pollio & Andrea Caricasole

  6. Structural and Computational Biology, EMBL, Heidelberg, Germany

    Venkata P Satagopam & Reinhard Schneider

  7. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg

    Venkata P Satagopam & Reinhard Schneider

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  1. Maria Jimenez-Sanchez
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Contributions

M.J.-S. performed most post-screen cell biology experiments. W.L. and S.I. performed the Drosophila experiments. M.H. and B.S. performed the cell-based screen. A.F., T.E.D. and C.X performed the zebrafish experiments, and A.F. supervised these. A.T., E.G.-C., V.P.S. and R.S. performed the bioinformatics analyses. F.M. performed the chaperone transcription array experiments and nonradioactive pulse-chase. E.G.-C. and F.H. participated in experimental design of the screen. F.H., G.L., D.D., L.M. and G.P. generated and validated the stable cell lines for the screen. G.M., C.C. and A.N. synthesized and analyzed the compounds. M.A. performed the selection of compound for high-throughput screening and supported the hit-to-lead optimization by in silico drug design methodologies. V.P. optimized glutaminyl cyclase enzymatic assays for compound screening. G.L.S. and N.P.C. performed in vitro ADME experiments. C.S. provided support for experiments at Siena Biotech. C.O.K. supervised Drosophila experiments. G.P. also supervised molecular biology activities at Siena Biotech. A.C. supervised primary screen and chemical biology. D.C.R. supervised cell biology, Drosophila and zebrafish experiments. D.C.R and A.C. conceived the project and coordinated work between sites with assistance from G.P., M.J.-S. and D.C.R., and A.C drafted the manuscript, which was commented on by all authors.

Corresponding authors

Correspondence to Andrea Caricasole or David C Rubinsztein.

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Competing interests

A.T., E.G.-C., G.L., F.H., D.D., L.M., G.P., G.M., C.C., A.N., M.A., G.L.S., N.P.C., V.P., C.S. and A.C. were employed by Siena Biotech; M.H. and B.S. were employed by Cenix BioScience GmbH.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–18 and Supplementary Table 1 (PDF 4464 kb)

Supplementary Dataset 1

List of 257 human genes obtained in HEK293 siRNA screen and its validation in Drosophila (PDF 240 kb)

Supplementary Dataset 2

List of RNAi Drosophila lines that rescued Q48-eyedegeneration and their effect on GFP levels (PDF 81 kb)

Supplementary Dataset 3

Complete results from heat shock protein PCR array (PDF 116 kb)

Supplementary Note 1

Details for primary high-throughput siRNA screen development and analysis (PDF 72 kb)

Supplementary Note 2

Detailed synthesis and characterization of QPCT inhibitors (PDF 147 kb)

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Jimenez-Sanchez, M., Lam, W., Hannus, M. et al. siRNA screen identifies QPCT as a druggable target for Huntington's disease. Nat Chem Biol 11, 347–354 (2015). https://doi.org/10.1038/nchembio.1790

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