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


Scheckel, Claudia; Imeri, Marigona; Schwarz, Petra; Aguzzi, Adriano (2020). Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons. eLife, 9:e62911.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, General Medicine
Language:English
Date:22 September 2020
Deposited On:30 Sep 2020 10:34
Last Modified:01 Nov 2020 17:10
Publisher:eLife Sciences Publications Ltd.
ISSN:2050-084X
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.7554/elife.62911
PubMed ID:32960170
Project Information:
  • : FunderH2020
  • : Grant ID706138
  • : Project TitlePrionomics - Systematic profiling of molecular changes during prion disease progression
  • : FunderH2020
  • : Grant ID670958
  • : Project TitlePRION2020 - Function and malfunction of the prion protein
  • : FunderSNSF
  • : Grant IDCRSII5_183563
  • : Project TitlePrP and its receptor GPR126: guardians of axomyelinic integrity and druggable targets against demyelinating diseases
  • : FunderSNSF
  • : Grant ID31003A_179040
  • : Project TitleThe prion protein in health and disease
  • : FunderCRPP
  • : Grant ID
  • : Project TitleSmall RNAs
  • : FunderCRPP
  • : Grant ID
  • : Project TitleHHLD
  • : FunderNOMIS Foundation
  • : Grant ID
  • : Project TitleDistinguished Scientist Award
  • : Project Websitehttps://nomisfoundation.ch/people/adriano-aguzzi/

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