ArticleProceedings of the National Academy of Sciences of the United States of America2021
Mechanism of misfolding of the human prion protein revealed by a pathological mutation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 42 citations in OpenAlex.
- Trends in the Engineering of Adeno-Associated Virus (AAV) for Precision Gene Delivery to the Central Nervous System (CNS).International journal of molecular sciences · 2026Review
- Copper Coordination to the Prion Fragment (95-126): Implications for Neurodegenerative Diseases.International journal of molecular sciences · 2026Article
- Structural and cellular properties of human prion protein oligomers.Communications biology · 2025Article
- Structure and Dynamics of the Misfolding Intermediate in the Pathogenic T183A Prion Protein Mutant.Journal of chemical theory and computation · 2025Article
- Chameleonic Nature of Aβ: Implications for Alzheimer's and Other Amyloid Diseases.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Review
- Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Overview of Metformin and Neurodegeneration: A Comprehensive Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Unsuccessful transmissions of atypical genetic Creutzfeldt-Jakob disease (PRNP p.T183A-129M) in transgenic mice.Acta neuropathologica · 2024Article
- Unfolding Mechanism and Fibril Formation Propensity of Human Prion Protein in the Presence of Molecular Crowding Agents.International journal of molecular sciences · 2024Article
- Article
- Realization of Amyloid-like Aggregation as a Common Cause for Pathogenesis in Diseases.Life (Basel, Switzerland) · 2023Review
- Review
- Intrinsic determinants of prion protein neurotoxicity inFrontiers in molecular neuroscience · 2023Review
- Antibody binding modulates the dynamics of the membrane-bound prion protein.Biophysical journal · 2022Article
- Multi-eGO: An in silico lens to look into protein aggregation kinetics at atomic resolution.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Investigating neurological symptoms of infectious diseases like COVID-19 leading to a deeper understanding of neurodegenerative disorders such as Parkinson's disease.Frontiers in neurology · 2022Review
- Identification of Two Early Folding Stage Prion Non-Local Contacts Suggested to Serve as Key Steps in Directing the Final Fold to Be Either Native or Pathogenic.International journal of molecular sciences · 2021Article
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Authors and funding
6 authors at 2 institutions in 3 countries.
Funding
Abstract
The misfolding and aggregation of the human prion protein (PrP) is associated with transmissible spongiform encephalopathies (TSEs). Intermediate conformations forming during the conversion of the cellular form of PrP into its pathological scrapie conformation are key drivers of the misfolding process. Here, we analyzed the properties of the C-terminal domain of the human PrP (huPrP) and its T183A variant, which is associated with familial forms of TSEs. We show that the mutation significantly enhances the aggregation propensity of huPrP, such as to uniquely induce amyloid formation under physiological conditions by the sole C-terminal domain of the protein. Using NMR spectroscopy, biophysics, and metadynamics simulations, we identified the structural characteristics of the misfolded intermediate promoting the aggregation of T183A huPrP and the nature of the interactions that prevent this species to be populated in the wild-type protein. In support of these conclusions, POM antibodies targeting the regions that promote PrP misfolding were shown to potently suppress the aggregation of this amyloidogenic mutant.
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