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Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice


Kaczmarczyk, Lech; Schleif, Melvin; Dittrich, Lars; Williams, Rhiannan H; Koderman, Maruša; Bansal, Vikas; Rajput, Ashish; Schulte, Theresa; Jonson, Maria; Krost, Clemens; Testaquadra, Fabio J; Bonn, Stefan; Jackson, Walker S (2022). Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice. PLoS Pathogens, 18(8):e1010747.

Abstract

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific cell types and brain regions. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite appearing normal. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated reduced synthesis of ribosomal and mitochondrial components, 2) glutamatergic neurons showed increased expression of cytoskeletal genes, and 3) GABAergic neurons revealed reduced expression of circadian rhythm genes. These data demonstrate that early translatome responses to neurodegeneration emerge prior to conventional markers of disease and are cell type-specific. Therapeutic strategies may need to target multiple pathways in specific populations of cells, early in disease.

Abstract

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific cell types and brain regions. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite appearing normal. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated reduced synthesis of ribosomal and mitochondrial components, 2) glutamatergic neurons showed increased expression of cytoskeletal genes, and 3) GABAergic neurons revealed reduced expression of circadian rhythm genes. These data demonstrate that early translatome responses to neurodegeneration emerge prior to conventional markers of disease and are cell type-specific. Therapeutic strategies may need to target multiple pathways in specific populations of cells, early in disease.

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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
Scopus Subject Areas:Life Sciences > Parasitology
Life Sciences > Microbiology
Life Sciences > Immunology
Life Sciences > Molecular Biology
Life Sciences > Genetics
Life Sciences > Virology
Uncontrolled Keywords:Virology, Genetics, Molecular Biology, Immunology, Microbiology, Parasitology
Language:English
Date:12 August 2022
Deposited On:14 Feb 2023 13:41
Last Modified:30 Jan 2024 02:43
Publisher:Public Library of Science (PLoS)
ISSN:1553-7366
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.ppat.1010747
PubMed ID:35960762
Project Information:
  • : FunderDeutsches Zentrum für Neurodegenerative Erkrankungen
  • : Grant ID
  • : Project Title
  • : FunderDeutsches Zentrum für Neurodegenerative Erkrankungen
  • : Grant ID
  • : Project Title
  • : FunderKnut och Alice Wallenbergs Stiftelse
  • : Grant ID
  • : Project Title
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)