ArticleThe EMBO journal2011
Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry.
Article in The EMBO journal, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
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
65 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 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
- Reduction of RAD23A extends lifespan and mitigates pathology in a mouse model of TDP-43 proteinopathy.Nature communications · 2026Article
- Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.Acta neuropathologica communications · 2025Article
- Protein quality control systems in neurodegeneration - culprits, mitigators, and solutions?Frontiers in neurology · 2025Review
- Trehalose Promotes Clearance of Proteotoxic Aggregation of Neurodegenerative Disease-Associated Aberrant Proteins.Molecular neurobiology · 2024Article
- VCP/p97 mediates nuclear targeting of non-ER-imported prion protein to maintain proteostasis.Life science alliance · 2024Article
- Proteotoxic stress and the ubiquitin proteasome system.Seminars in cell & developmental biology · 2024Review
- Role of NFE2L1 in the Regulation of Proteostasis: Implications for Aging and Neurodegenerative Diseases.Biology · 2023Review
- Allosteric regulation of the 20S proteasome by the Catalytic Core Regulators (CCRs) family.Nature communications · 2023Article
- Role of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance.Molecular neurobiology · 2022Review
- Direct Analysis of Mitochondrial Damage Caused by Misfolded/Destabilized Proteins.International journal of molecular sciences · 2022Article
- Raising cGMP restores proteasome function and myelination in mice with a proteotoxic neuropathy.Brain : a journal of neurology · 2022Article
- Proteostasis unbalance in prion diseases: Mechanisms of neurodegeneration and therapeutic targets.Frontiers in neuroscience · 2022Review
- Advances in Proteasome Enhancement by Small Molecules.Biomolecules · 2021Review
- Mechanisms That Activate 26S Proteasomes and Enhance Protein Degradation.Biomolecules · 2021Review
- Stress-induced NEDDylation promotes cytosolic protein aggregation through HDAC6 in a p62-dependent manner.iScience · 2021Article
- Sis1 potentiates the stress response to protein aggregation and elevated temperature.Nature communications · 2020Article
- Proteasome Biology: Chemistry and Bioengineering Insights.Polymers · 2020Review
- From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins.Biomolecules · 2020Review
5 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
Abstract
Prion diseases are associated with the conversion of cellular prion protein (PrP(C)) to toxic β-sheet isoforms (PrP(Sc)), which are reported to inhibit the ubiquitin-proteasome system (UPS). Accordingly, UPS substrates accumulate in prion-infected mouse brains, suggesting impairment of the 26S proteasome. A direct interaction between its 20S core particle and PrP isoforms was demonstrated by immunoprecipitation. β-PrP aggregates associated with the 20S particle, but did not impede binding of the PA26 complex, suggesting that the aggregates do not bind to its ends. Aggregated β-PrP reduced the 20S proteasome's basal peptidase activity, and the enhanced activity induced by C-terminal peptides from the 19S ATPases or by the 19S regulator itself, including when stimulated by polyubiquitin conjugates. However, the 20S proteasome was not inhibited when the gate in the α-ring was open due to a truncation mutation or by association with PA26/PA28. These PrP aggregates inhibit by stabilising the closed conformation of the substrate entry channel. A similar inhibition of substrate entry into the proteasome may occur in other neurodegenerative diseases where misfolded β-sheet-rich proteins accumulate.
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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.