Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Prion diseases (PrDs) involve misfolded prion protein (PrPSc) aggregates in both the brain and extraneural organs.
• The extent and nature of extraneural pathology in PrDs remain incompletely understood.
• Investigating extraneural tissues is crucial for a comprehensive understanding of prion disease progression.

Purpose of the Study:

• To investigate extraneural gene expression changes during prion disease progression.
• To identify specific molecular alterations in skeletal muscle, spleen, and blood.
• To determine if observed changes are unique to prion diseases.

Main Methods:

• mRNA sequencing of skeletal muscle, spleen, and blood from prion-inoculated mice at eight timepoints.
• Analysis of gene expression patterns throughout disease progression.
• Comparison of findings with human neurodegenerative diseases (ALS, AD, DLB).

Main Results:

• Significant gene expression changes were detected in all three organs, with skeletal muscle showing the most consistent alterations.
• Glutamate-ammonia ligase (GLUL) was uniformly upregulated in skeletal muscle across different prion strains and in human sporadic Creutzfeldt-Jakob disease.
• GLUL dysregulation led to altered glutamate/glutamine metabolism and reduced glutamate levels in skeletal muscle, a finding not observed in other neurodegenerative diseases.

Conclusions:

• Prion infections induce significant extraneural gene expression changes, particularly in skeletal muscle.
• Dysregulation of glutamate-ammonia ligase (GLUL) and associated metabolic alterations are specific hallmarks of prion disease in skeletal muscle.
• These findings highlight an unexpected metabolic dimension to prion infections and suggest GLUL's role in prion-affected muscle.