ArticleScience translational medicine2013
Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice.
Article in Science translational medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 359 papers.
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Who cites it
359 citing papers in PubMed.
- DNL343 and Disease Progression in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.JAMA network open · 2026Trial
- eIF5A and polyamines restrict mRNA levels in response to ribosome stalls.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Using human 3D organoid models to gain mechanistic insight in motor neuron diseases.Nature reviews. Neuroscience · 2026Review
- Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.Signal transduction and targeted therapy · 2026Review
- Diverse stresses differentially regulate rRNA biogenesis and mRNA translation.Nucleic acids research · 2026Article
- Theory and simulations of delayed stochastic and deterministic models of prion diseases.Journal of mathematical biology · 2026Article
- Progressive Supranuclear Palsy PERK Haplotype B Selectively Translates DLX1 Promoting Tau Toxicity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- The PERK inhibitor GSK2606414 evokes developmental defects in zebrafish consistent with Wolcott-Rallison syndrome phenotypes.Pharmacological reports : PR · 2026Article
- Neurons with granulovacuolar degeneration bodies are resilient to tau-induced protein synthesis impairment.Science advances · 2026Article
- Proteomic Analysis of Cerebrospinal Fluid from Severe COVID-19 Patients Reveals Prognostic Biomarkers Associated with Disease Outcome.Proteomics. Clinical applications · 2026Article
- Function and regulation of the mitochondrial stress response.Nature structural & molecular biology · 2026Review
- Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers.Biomedicines · 2026Review
- Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.Nature genetics · 2026Article
- The integrated stress response in pancreatic β-cell failure in diabetes: from molecular mechanisms to precision therapeutics.Frontiers in endocrinology · 2026Review
- Review
- CK2α Regulates Endoplasmic Reticulum Stress-Mediated Mitophagy via the PERK/ATF4/CHOP Pathway in Rotenone-Treated SH-SY5Y Cells.Molecular neurobiology · 2025Article
- ER stress tolerance is regulated by copper-dependent PERK kinase activity.Cell reports · 2025Article
- Pathological and Functional Brain Amyloids: A New Concept Explaining the Differences.International journal of molecular sciences · 2025Review
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Integrated stress response in Behçet disease: expression analyses in peripheral blood and synovial monocytes.Rheumatology international · 2025Article
299 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors.
Funding
Abstract
During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.
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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.