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Rapid ex vivo reverse genetics identifies the essential determinants of prion protein toxicity
Open accessPreprint — published as 10.1111/bpa.13130 · Paper page
Abstract
The cellular prion protein PrP C mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrP C (GDL) can also initiate neurotoxicity by inducing an intramolecular R 208 -H 140 hydrogen bond (“H-latch”) between the α2-α3 and β2-α2 loops of PrP C . Importantly, GDL that suppress the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced nineteen individual PrP C variants to PrP C -deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K 27 or R 27 ) within PrP C . Alanine substitution of K 27 also prevented the toxicity of PrP C mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrP C . K 27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein
Balducci, C., Beeg, M., Stravalaci, M., Bastone, A., Sclip, A., Biasini, E., Tapella, L., Colombo, L., Manzoni, C., Borsello, T., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911829107 · Cited by 466
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Metadata
- Authors
- Reimann, R. R., Puzio, M., Rosati, A., Emmenegger, M., Schneider, B. L., Valdés, P., Huang, D., Caflisch, A., & Aguzzi, A.
- Affiliations
- University of Zurich (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Reimann, Regina R.
- Aguzzi, Adriano
- ORCID
- Venue
- Brain Pathology
- Publisher
- openRxiv
- Published
- 2022-10-07
- Volume
- 33
- Issue
- 2
- Pages
- e13130-e13130
- ISSN
- 1015-6305 (ISSN-L)
- PMC
- PMC10041163
- OpenAlex
- W4308182087
- Cited by
- 4
- References
- 2
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 1
- FWCI
- 0.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Brain Pathology (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- Michael J. Fox Foundation for Parkinson's Research (ID MJFF‐022156, MJFF-022156)
- Fondazione Gelu
- Human Frontier Science Program (ID RGP0001/2022)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (207872, 179040, 183563)
- Stavros Niarchos Foundation
- Universität Zürich
- Baugarten Stiftung (USZF27101)
- NOMIS Stiftung
- Universitätsspital Zürich (2017DRI17, INOV00096)
- Innosuisse - Schweizerische Agentur für Innovationsförderung
- Horizon 2020 Framework Programme
- H2020 European Research Council (H2020, 670958)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Internal Medicine › Amyloidosis: Diagnosis, Treatment, Outcomes
- Keywords
- cellular prion protein, intramolecular hydrogen bonding, neurotoxicity, cationic residues, prion infection, neurodegeneration
- MeSH terms
- Prion Proteins, Animals, Antibodies, Prions, Prion Diseases, Neurodegenerative Diseases, Mice, Reverse Genetics
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