ArticleActa neuropathologica2016
Prion-mediated neurodegeneration is associated with early impairment of the ubiquitin-proteasome system.
Article in Acta neuropathologica, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Deubiquitinating enzymes-mediated post-translational modifications of ferroptosis regulates cancer drug resistance.Discover oncology · 2026Review
- Bovine Spongiform Encephalopathy: An Integrated Review of Prion Mechanisms, Neuroanatomy, and Control.Veterinary sciences · 2026Review
- Genome-wide screens identify core regulators of cell surface prion protein expression.Scientific reports · 2026Article
- Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2026Review
- Exploring immunotherapeutic strategies for neurodegenerative diseases: a focus on Huntington's disease and Prion diseases.Acta pharmacologica Sinica · 2025Review
- Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs.ACS pharmacology & translational science · 2025Review
- New Therapeutic Modalities in Prion Diseases.Sub-cellular biochemistry · 2025Review
- Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner.Autophagy · 2024Article
- Structural Variations of Prions and Prion-like Proteins Associated with Neurodegeneration.Current issues in molecular biology · 2024Review
- Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Endoplasmic reticulum stress and ubiquitin-proteasome system impairment in natural scrapie.Frontiers in molecular neuroscience · 2023Article
- Article
- The E3 Ubiquitin Ligase TRAF6 Interacts with the Cellular Prion Protein and Modulates Its Solubility and Recruitment to Cytoplasmic p62/SQSTM1-Positive Aggresome-Like Structures.Molecular neurobiology · 2022Article
- Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions.Nature reviews. Neurology · 2022Review
- Advances in Proteasome Enhancement by Small Molecules.Biomolecules · 2021Review
- Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases.International journal of molecular sciences · 2021Review
- Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease.International journal of molecular sciences · 2021Article
- Mode of targeting to the proteasome determines GFP fate.The Journal of biological chemistry · 2020Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of misfolded prion protein (PrP(Sc)) in the brain. The critical relationship between aberrant protein misfolding and neurotoxicity currently remains unclear. The accumulation of aggregation-prone proteins has been linked to impairment of the ubiquitin-proteasome system (UPS) in a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington's diseases. As the principal route for protein degradation in mammalian cells, this could have profound detrimental effects on neuronal function and survival. Here, we determine the temporal onset of UPS dysfunction in prion-infected Ub(G76V)-GFP reporter mice, which express a ubiquitin fusion proteasome substrate to measure in vivo UPS activity. We show that the onset of UPS dysfunction correlates closely with PrP(Sc) deposition, preceding earliest behavioural deficits and neuronal loss. UPS impairment was accompanied by accumulation of polyubiquitinated substrates and found to affect both neuronal and astrocytic cell populations. In prion-infected CAD5 cells, we demonstrate that activation of the UPS by the small molecule inhibitor IU1 is sufficient to induce clearance of polyubiquitinated substrates and reduce misfolded PrP(Sc) load. Taken together, these results identify the UPS as a possible early mediator of prion pathogenesis and promising target for development of future therapeutics.
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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.