ArticleNature chemical biology2015
siRNA screen identifies QPCT as a druggable target for Huntington's disease.
Article in Nature chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 95 citations in OpenAlex.
- Inhibition of the QPCT-PDIA4 axis rescues ΔF508 and N1303K CFTR in cystic fibrosis.Nature communications · 2026Article
- Proteomic profiling in cerebrospinal fluid reveal biomarkers for shunt outcome in idiopathic normal-pressure hydrocephalus.Journal of advanced research · 2026Article
- Immunomodulatory functions of glutaminyl cyclases QPCTL and QPCT.Frontiers in immunology · 2026Review
- Nonlinear combinatorial analysis of blood transcriptomes identifies PRKAR1A as a regulator of TDP-43 pathophysiology in amyotrophic lateral sclerosis.Biology methods & protocols · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Mitogen-activated protein kinase pathway and four genes involved in the development of benign prostatic hyperplasia:Frontiers in immunology · 2025Article
- Small HSPs at the crossroad between protein aggregation, autophagy and unconventional secretion: clinical implications and potential therapeutic opportunities in the context of neurodegenerative diseases.Frontiers in cell and developmental biology · 2025Review
- Article
- Metal Ion Binding to Human Glutaminyl Cyclase: A Structural Perspective.International journal of molecular sciences · 2024Article
- Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence.The Plant cell · 2023Article
- The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein.Human molecular genetics · 2023Article
- Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis.The Journal of cell biology · 2023Article
- Development and evolution of human glutaminyl cyclase inhibitors (QCIs): an alternative promising approach for disease-modifying treatment of Alzheimer's disease.Frontiers in aging neuroscience · 2023Review
- Molecular mechanisms of resistance to tyrosine kinase inhibitor in clear cell renal cell carcinoma.International journal of urology : official journal of the Japanese Urological Association · 2022Review
- Emerging degrader technologies engaging lysosomal pathways.Chemical Society reviews · 2022Review
- Modifier pathways in polyglutamine (PolyQ) diseases: from genetic screens to drug targets.Cellular and molecular life sciences : CMLS · 2022Review
- Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.Nature communications · 2022Article
- QPCTL regulates macrophage and monocyte abundance and inflammatory signatures in the tumor microenvironment.Oncoimmunology · 2022Article
- Repurposing FDA-Approved Compounds for the Discovery of Glutaminyl Cyclase Inhibitors as Drugs Against Alzheimer's Disease.ChemistryOpen · 2021Article
- New Avenues for the Treatment of Huntington's Disease.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
29 authors at 4 institutions in 4 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.