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.

Data availability

Sequencing data has been deposited in GEO under accession code GSE149805.

Article and author information

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Claudia Scheckel

Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

For correspondence
claudia.scheckel@usz.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1649-8486
Marigona Imeri

Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Petra Schwarz

Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1686-8624
Adriano Aguzzi

Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

For correspondence
adriano.aguzzi@usz.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0344-6708

Funding

H2020 Marie Skłodowska-Curie Actions (706138)

Claudia Scheckel

H2020 European Research Council (670958)

Adriano Aguzzi

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschungf (179040)

Adriano Aguzzi

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (183563)

Adriano Aguzzi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments were performed in compliance with the Swiss Animal Protection Law, under the approval of the Veterinary office of the Canton Zurich (animal permits ZH040/15, ZH139/16).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.