siRNA screen identifies QPCT as a druggable target for Huntington's disease
| Autor: | Nicola P. Caradonna, Giulia Lazzeroni, David C. Rubinsztein, Fiona M. Menzies, Alessia Tarditi, Venkata P. Satagopam, Valentina Porcari, Angeleen Fleming, Reinhard Schneider, Freddy Heitz, Chiara Caramelli, Birte Sönnichsen, Maria Jimenez-Sanchez, Carla Scali, Sara Imarisio, Michael Hannus, Giuseppe Pollio, Wun Lam, Daniela Diamanti, Catherine K. Xu, Eduardo Gonzalez-Couto, Arianna Nencini, Gian Luca Sardone, Andrea Caricasole, Cahir J. O'Kane, Matteo Andreini, Luisa Massai, Guido Marconi, Teresa Ed Dami |
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| Přispěvatelé: | Fleming, Angeleen [0000-0003-3721-7126], O'Kane, Cahir [0000-0002-3488-2078], Rubinsztein, David [0000-0001-5002-5263], Apollo - University of Cambridge Repository, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center] |
| Rok vydání: | 2014 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Huntingtin In silico Green Fluorescent Proteins Druggability Drug Evaluation Preclinical Nerve Tissue Proteins Biology Biochemistry biophysics & molecular biology [F05] [Life sciences] medicine.disease_cause Article 03 medical and health sciences Mice 0302 clinical medicine Huntington's disease mental disorders medicine Huntingtin Protein Animals Humans Enzyme Inhibitors RNA Small Interfering Biochimie biophysique & biologie moléculaire [F05] [Sciences du vivant] Molecular Biology Zebrafish Cells Cultured 030304 developmental biology Genetics Neurons 0303 health sciences Mutation Computational Biology alpha-Crystallin B Chain Cell Biology Polyglutamine tract medicine.disease biology.organism_classification Aminoacyltransferases 3. Good health Cell biology Mice Inbred C57BL Huntington Disease Drosophila 030217 neurology & neurosurgery |
| Zdroj: | Nature chemical biology Nature chemical biology, 11(5), 347–354. (2015). |
| ISSN: | 1552-4469 |
| Popis: | Huntington’s disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified novel 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 which also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone alpha B-crystallin and reduced the aggregation of diverse proteins. We generated novel QPCT inhibitors using in silico methods followed by in vitro screens, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a novel HD druggable target affecting mutant huntingtin aggregation, and provide proof-of-principle for a discovery pipeline from druggable genome screen to drug development. |
| Databáze: | OpenAIRE |
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