Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons

  1. Claudia Scheckel  Is a corresponding author
  2. Marigona Imeri
  3. Petra Schwarz
  4. Adriano Aguzzi  Is a corresponding author
  1. University Hospital Zurich, Switzerland

Abstract

Prion diseases are caused by PrPSc, a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrPSc 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

Author details

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1649-8486
  2. Marigona Imeri

    Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Petra Schwarz

    Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1686-8624
  4. 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.
    ORCID icon "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.

Reviewing Editor

  1. J Paul Taylor, St Jude Children's Research Hospital, United States

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).

Version history

  1. Received: September 10, 2020
  2. Accepted: September 16, 2020
  3. Accepted Manuscript published: September 22, 2020 (version 1)
  4. Version of Record published: September 30, 2020 (version 2)

Copyright

© 2020, Scheckel et al.

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.

Metrics

  • 2,783
    views
  • 412
    downloads
  • 30
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Claudia Scheckel
  2. Marigona Imeri
  3. Petra Schwarz
  4. Adriano Aguzzi
(2020)
Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons
eLife 9:e62911.
https://doi.org/10.7554/eLife.62911

Share this article

https://doi.org/10.7554/eLife.62911

Further reading

    1. Neuroscience
    Ivan Tomić, Paul M Bays
    Research Article

    Probing memory of a complex visual image within a few hundred milliseconds after its disappearance reveals significantly greater fidelity of recall than if the probe is delayed by as little as a second. Classically interpreted, the former taps into a detailed but rapidly decaying visual sensory or ‘iconic’ memory (IM), while the latter relies on capacity-limited but comparatively stable visual working memory (VWM). While iconic decay and VWM capacity have been extensively studied independently, currently no single framework quantitatively accounts for the dynamics of memory fidelity over these time scales. Here, we extend a stationary neural population model of VWM with a temporal dimension, incorporating rapid sensory-driven accumulation of activity encoding each visual feature in memory, and a slower accumulation of internal error that causes memorized features to randomly drift over time. Instead of facilitating read-out from an independent sensory store, an early cue benefits recall by lifting the effective limit on VWM signal strength imposed when multiple items compete for representation, allowing memory for the cued item to be supplemented with information from the decaying sensory trace. Empirical measurements of human recall dynamics validate these predictions while excluding alternative model architectures. A key conclusion is that differences in capacity classically thought to distinguish IM and VWM are in fact contingent upon a single resource-limited WM store.

    1. Neuroscience
    Emilio Salinas, Bashirul I Sheikh
    Insight

    Our ability to recall details from a remembered image depends on a single mechanism that is engaged from the very moment the image disappears from view.