ArticlePLoS pathogens2009
Selective processing and metabolism of disease-causing mutant prion proteins.
Article in PLoS pathogens, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 113 citations in OpenAlex.
- Mechanisms of Quality Control in GPI-Anchored Proteins: The Central Role of the Lipid Anchor.International journal of molecular sciences · 2026Review
- Prion protein (PrP) profiles in blood and CSF: insights into pre-symptomatic and symptomatic prion disease.Brain communications · 2026Article
- TMED9 coordinates the clearance of misfolded GPI-anchored proteins out of the ER and into the Golgi.PLoS biology · 2025Article
- Competition for calnexin binding regulates secretion and turnover of misfolded GPI-anchored proteins.The Journal of cell biology · 2023Article
- Dysregulated proteostasis network in neuronal diseases.Frontiers in cell and developmental biology · 2023Review
- Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS.JCI insight · 2022Article
- Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins.Journal of cell science · 2022Article
- Endosomal sorting drives the formation of axonal prion protein endoggresomes.Science advances · 2021Article
- Membrane dynamics and protein targets of lipid droplet microautophagy during ER stress-induced proteostasis in the budding yeast,Autophagy · 2021Article
- Potential Physiological Relevance of ERAD to the Biosynthesis of GPI-Anchored Proteins in Yeast.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
- A New Take on Prion Protein Dynamics in Cellular Trafficking.International journal of molecular sciences · 2020Review
- Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation.Molecular neurobiology · 2020Article
- Mutant-selective topologic conversion facilitates selective degradation of a pathogenic prion isoform.Cell death and differentiation · 2020Article
- Protein folding state-dependent sorting at the Golgi apparatus.Molecular biology of the cell · 2019Article
- Endoplasmic Reticulum Export of GPI-Anchored Proteins.International journal of molecular sciences · 2019Review
- Misfolded GPI-anchored proteins are escorted through the secretory pathway by ER-derived factors.eLife · 2019Article
- Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?Current aging science · 2019Review
- Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases.International journal of molecular sciences · 2018Review
- Effect of the unfolded protein response on ER protein export: a potential new mechanism to relieve ER stress.Cell stress & chaperones · 2018Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Prion diseases are fatal neurodegenerative disorders caused by aberrant metabolism of the cellular prion protein (PrP(C)). In genetic forms of these diseases, mutations in the globular C-terminal domain are hypothesized to favor the spontaneous generation of misfolded PrP conformers (including the transmissible PrP(Sc) form) that trigger downstream pathways leading to neuronal death. A mechanistic understanding of these diseases therefore requires knowledge of the quality control pathways that recognize and degrade aberrant PrPs. Here, we present comparative analyses of the biosynthesis, trafficking, and metabolism of a panel of genetic disease-causing prion protein mutants in the C-terminal domain. Using quantitative imaging and biochemistry, we identify a misfolded subpopulation of each mutant PrP characterized by relative detergent insolubility, inaccessibility to the cell surface, and incomplete glycan modifications. The misfolded populations of mutant PrPs were neither recognized by ER quality control pathways nor routed to ER-associated degradation despite demonstrable misfolding in the ER. Instead, mutant PrPs trafficked to the Golgi, from where the misfolded subpopulation was selectively trafficked for degradation in acidic compartments. Surprisingly, selective re-routing was dependent not only on a mutant globular domain, but on an additional lysine-based motif in the highly conserved unstructured N-terminus. These results define a specific trafficking and degradation pathway shared by many disease-causing PrP mutants. As the acidic lysosomal environment has been implicated in facilitating the conversion of PrP(C) to PrP(Sc), our identification of a mutant-selective trafficking pathway to this compartment may provide a cell biological basis for spontaneous generation of PrP(Sc) in familial prion disease.
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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.