Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons
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Abstract
Prion diseases are caused by PrP Sc , a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrP Sc causes a robust, reproducible and specific disease manifestation. Here, we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type-specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.
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While microglia expression profiles change considerably over the course of disease in a region-dependent manner, neuronal phenotypes remain comparatively stable.
“Interestingly, while microglia expression profiles changed considerably of the course of disease in a region-dependent manner, neuronal phenotypes remained comparatively stable [37,38].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [38]
Progressive dysregulation of glia cells including microglia can be demonstrated on the gene expression level.
“Progressive dysregulation of glia cells including microglia could also be demonstrated on the gene expression level using novel techniques [37,38].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [38]
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Caredio, D., Mariutti, G., Polzer, L. K., Cerisoli, M., Gatta, B., Laimeche, Y., Miracca, G., Emmenegger, M., Hruška-Plocháň, M., Polymenidou, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.11.637592 · Cited by 1 · see citing works
Self-citationMulti-omic analysis of the aging mouse brain
Kluever, V. (2021) · doi:10.53846/goediss-9022
Translational regulation enhances distinction of cell types in the nervous system
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Self-citationReactive Microglia and Astrocytes as Therapeutic Targets in Prion Diseases
Makarava, N., Kushwaha, R., & Baskakov, I. V. (2025) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-97055-9_8
Ablation of progranulin augments microglial activation and accelerates prion progression
Li, B., Shi, Y., Hou, W., Guan, H., Li, J., Yi, T., Li, W., Cai, D., Schwarz, P., Aguzzi, A., et al. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02128-3
Self-citationMakarava, N., Mychko, O., Chang, J. C., Molesworth, K., & Baskakov, I. V. (2021) · Figshare · doi:10.6084/m9.figshare.14583799
Slota, J. A., Sajesh, B. V., Frost, K. F., Medina, S. J., & Booth, S. A. (2022) · Figshare · doi:10.6084/m9.figshare.21532645
Makarava, N., Mychko, O., Chang, J. C., Molesworth, K., & Baskakov, I. V. (2021) · Figshare · doi:10.6084/m9.figshare.14583817
- Authors
- Scheckel, C., Imeri, M., Schwarz, P., & Aguzzi, A.
- Affiliations
- University of Zurich (CH)
- Corresponding author
- Scheckel, Claudia
- Aguzzi, Adriano
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-09-22
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7527237
- OpenAlex
- W3087279494
- Cited by
- 57
- References
- 40
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 13 · 2023: 6 · 2022: 14 · 2021: 12 · 2020: 1
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- H2020 Marie Skłodowska-Curie Actions (706138)
- H2020 European Research Council (670958)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (179040, 183563)
- NOMIS Foundation (Distinguished Scientist Award)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- prion disease, ribosome profiling, glial cells, astrocytes, microglia, neurons, cell type-specific translation, neurodegeneration, translating ribosome affinity purification
- MeSH terms
- Animals, Mice, Transgenic, Neuroglia, Neurons, Recombinant Fusion Proteins, Ribosomal Proteins, Ribosomes, Prion Diseases, Green Fluorescent Proteins, Mice
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