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Skeletal-Muscle Glutamine Synthase is Upregulated in Preclinical Prion Diseases


Caredio, Davide; Koderman, Maruša; Frontzek, Karl; Sorce, Silvia; Nuvolone, Mario; Bremer, Juliane; Schwarz, Petra; Sellitto, Stefano; Streichenberger, Nathalie; Scheckel, Claudia; Aguzzi, Adriano (2023). Skeletal-Muscle Glutamine Synthase is Upregulated in Preclinical Prion Diseases. bioRxiv 564879, Cold Spring Harbor Laboratory.

Abstract

In prion diseases, aggregates of misfolded prion protein (PrP$^{Sc}$) accumulate not only in the brain but can also be found in various extraneural tissues. This raises the question whether prion-specific pathologies arise also in these tissues. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected consistent gene-expression changes in all three organs, with skeletal muscle showing the most uniform alterations during disease progression. The glutamate synthetase (GLUL) gene was monotonically upregulated in skeletal muscle of mice infected with three different scrapie prion strains (RML, ME7 and 22L) and in human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer’s disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. Besides pointing to unrecognized metabolic implications of prion infections, these findings suggest that GLUL could represent an accessible biomarker of prion disease progression, particularly during the preclinical stages of disease, and might be useful for monitoring the efficacy of experimental antiprion therapies.

Abstract

In prion diseases, aggregates of misfolded prion protein (PrP$^{Sc}$) accumulate not only in the brain but can also be found in various extraneural tissues. This raises the question whether prion-specific pathologies arise also in these tissues. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected consistent gene-expression changes in all three organs, with skeletal muscle showing the most uniform alterations during disease progression. The glutamate synthetase (GLUL) gene was monotonically upregulated in skeletal muscle of mice infected with three different scrapie prion strains (RML, ME7 and 22L) and in human sporadic Creutzfeldt-Jakob disease. GLUL dysregulation was accompanied by changes in glutamate/glutamine metabolism, leading to reduced glutamate levels in skeletal muscle. None of these changes were observed in skeletal muscle of humans with amyotrophic lateral sclerosis, Alzheimer’s disease, or dementia with Lewy bodies, suggesting that they are specific to prion diseases. Besides pointing to unrecognized metabolic implications of prion infections, these findings suggest that GLUL could represent an accessible biomarker of prion disease progression, particularly during the preclinical stages of disease, and might be useful for monitoring the efficacy of experimental antiprion therapies.

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Additional indexing

Item Type:Working Paper
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Language:English
Date:2 November 2023
Deposited On:27 Nov 2023 10:16
Last Modified:27 May 2024 15:23
Series Name:bioRxiv
Number of Pages:40
ISSN:2164-7844
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/2023.10.31.564879
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)