Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle

PLoS Pathog. 2024 Sep 11;20(9):e1012552. doi: 10.1371/journal.ppat.1012552. eCollection 2024 Sep.

Abstract

In prion diseases (PrDs), aggregates of misfolded prion protein (PrPSc) accumulate not only in the brain but also in extraneural organs. This raises the question whether prion-specific pathologies arise also extraneurally. Here we sequenced mRNA transcripts in skeletal muscle, spleen and blood of prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes in all three organs, with skeletal muscle showing the most consistent alterations. The glutamate-ammonia ligase (GLUL) gene exhibited uniform upregulation in skeletal muscles of mice infected with three distinct scrapie prion strains (RML, ME7, and 22L) and in victims of 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. These findings reveal an unexpected metabolic dimension of prion infections and point to a potential role for GLUL dysregulation in the glutamate/glutamine metabolism in prion-affected skeletal muscle.

MeSH terms

  • Animals
  • Creutzfeldt-Jakob Syndrome / genetics
  • Creutzfeldt-Jakob Syndrome / metabolism
  • Creutzfeldt-Jakob Syndrome / pathology
  • Female
  • Glutamate-Ammonia Ligase / metabolism
  • Glutamic Acid* / metabolism
  • Glutamine* / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal* / metabolism
  • Muscle, Skeletal* / pathology
  • Prion Diseases* / genetics
  • Prion Diseases* / metabolism

Substances

  • Glutamine
  • Glutamic Acid
  • Glutamate-Ammonia Ligase

Grants and funding

A.A. is supported by institutional core funding by the University of Zurich and the University Hospital of Zurich, a Distinguished Scientist Award of the NOMIS Foundation, an Advanced Grant of the European Research Council (ERC Prion2020 grant ID 278611) and grants from the GELU Foundation, the Swiss National Science Foundation (SNSF grant ID 179040 and grant ID 207872, Sinergia grant ID 183563), and the Human Frontiers Science Program (grant ID RGP0001/2022). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.