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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 ?B-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.

SUBMITTER: Jimenez-Sanchez M

PROVIDER: S-EPMC4696152 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Jimenez-Sanchez Maria M Lam Wun W Hannus Michael M Sönnichsen Birte B Imarisio Sara S Fleming Angeleen A Tarditi Alessia A Menzies Fiona F Dami Teresa Ed TE Xu Catherine C Gonzalez-Couto Eduardo E Lazzeroni Giulia G Heitz Freddy F Diamanti Daniela D Massai Luisa L Satagopam Venkata P VP Marconi Guido G Caramelli Chiara C Nencini Arianna A Andreini Matteo M Sardone Gian Luca GL Caradonna Nicola P NP Porcari Valentina V Scali Carla C Schneider Reinhard R Pollio Giuseppe G O'Kane Cahir J CJ Caricasole Andrea A Rubinsztein David C DC

Nature chemical biology 20150406 5

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 re ...[more]

PMID: 25848931

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Project description:Effective therapeutic approaches are urgently required to tackle the alarmingly poor survival outcomes in esophageal adenocarcinoma (EAC) patients. EAC originates from within the intestinal-type metaplasia, Barrett's esophagus, a condition arising on a background of gastroesophageal reflux disease and associated inflammation.This study used a druggable genome small interfering RNA (siRNA) screening library of 6022 siRNAs in conjunction with bioinformatics platforms, genomic studies of EAC tissues, somatic variation data of EAC from The Cancer Genome Atlas data of EAC, and pathologic and functional studies to define novel EAC-associated, and targetable, immune factors.By using a druggable genome library we defined genes that sustain EAC cell growth, which included an unexpected immunologic signature. Integrating Cancer Genome Atlas data with druggable siRNA targets showed a striking concordance and an EAC-specific gene amplification event associated with 7 druggable targets co-encoded at Chr6p21.1. Over-representation of immune pathway-associated genes supporting EAC cell growth included leukemia inhibitory factor, complement component 1, q subcomponent A chain (C1QA), and triggering receptor expressed on myeloid cells 2 (TREM2), which were validated further as targets sharing downstream signaling pathways through genomic and pathologic studies. Finally, targeting the triggering receptor expressed on myeloid cells 2-, C1q-, and leukemia inhibitory factor-activated signaling pathways (TYROBP-spleen tyrosine kinase and JAK-STAT3) with spleen tyrosine kinase and Janus-activated kinase inhibitor fostamatinib R788 triggered EAC cell death, growth arrest, and reduced tumor burden in NOD scid gamma mice.These data highlight a subset of genes co-identified through siRNA targeting and genomic studies of expression and somatic variation, specifically highlighting the contribution that immune-related factors play in support of EAC development and suggesting their suitability as targets in the treatment of EAC.

Dataset Information

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

Publications

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

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