ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2011
A nine amino acid domain is essential for mutant prion protein toxicity.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 58 citations in OpenAlex.
- Novel Prion Protein Gene (bioRxiv : the preprint server for biology · 2026Article
- Identification and initial characterization of novel prion protein gene (Frontiers in veterinary science · 2026Article
- Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease.Journal of neurochemistry · 2025Review
- Biological function of sialic acid and sialylation in human health and disease.Cell death discovery · 2024Review
- Effect of host and strain factors on α-synuclein prion pathogenesis.Trends in neurosciences · 2024Review
- Mechanisms of prion-induced toxicity.Cell and tissue research · 2023Review
- Rapid ex vivo reverse genetics identifies the essential determinants of prion protein toxicity.Brain pathology (Zurich, Switzerland) · 2023Article
- Beta-endoproteolysis of the cellular prion protein by dipeptidyl peptidase-4 and fibroblast activation protein.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Biological Functions of the Intrinsically Disordered N-Terminal Domain of the Prion Protein: A Possible Role of Liquid-Liquid Phase Separation.Biomolecules · 2021Review
- Protective anti-prion antibodies in human immunoglobulin repertoires.EMBO molecular medicine · 2020Article
- N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases.International journal of molecular sciences · 2020Review
- Intrinsic toxicity of the cellular prion protein is regulated by its conserved central region.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Structural Features of Heparin and Its Interactions With Cellular Prion Protein Measured by Surface Plasmon Resonance.Frontiers in molecular biosciences · 2020Article
- Review
- Altered Domain Structure of the Prion Protein Caused by CuStructure (London, England : 1993) · 2019Article
- Prion neurotoxicity.Brain pathology (Zurich, Switzerland) · 2019Review
- Application of high-throughput, capillary-based Western analysis to modulated cleavage of the cellular prion protein.The Journal of biological chemistry · 2019Article
- Identification of anti-prion drugs and targets using toxicity-based assays.Current opinion in pharmacology · 2019Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Transgenic mice expressing prion protein (PrP) molecules with several different internal deletions display spontaneous neurodegenerative phenotypes that can be dose-dependently suppressed by coexpression of wild-type PrP. Each of these deletions, including the largest one (Δ32-134), retains 9 aa immediately following the signal peptide cleavage site (residues 23-31; KKRPKPGGW). These residues have been implicated in several biological functions of PrP, including endocytic trafficking and binding of glycosaminoglycans. We report here on our experiments to test the role of this domain in the toxicity of deleted forms of PrP. We find that transgenic mice expressing Δ23-134 PrP display no clinical symptoms or neuropathology, in contrast to mice expressing Δ32-134 PrP, suggesting that residues 23-31 are essential for the toxic phenotype. Using a newly developed cell culture assay, we narrow the essential region to amino acids 23-26, and we show that mutant PrP toxicity is not related to the role of the N-terminal residues in endocytosis or binding to endogenous glycosaminoglycans. However, we find that mutant PrP toxicity is potently inhibited by application of exogenous glycosaminoglycans, suggesting that the latter molecules block an essential interaction between the N terminus of PrP and a membrane-associated target site. Our results demonstrate that a short segment containing positively charged amino acids at the N terminus of PrP plays an essential role in mediating PrP-related neurotoxicity. This finding identifies a protein domain that may serve as a drug target for amelioration of prion neurotoxicity.
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