Upregulation of Glutamate-Ammonia Ligase (GLUL) in Skeletal Muscle is a Distinctive Feature of Prion Diseases

Core Concepts

Prion diseases exhibit a unique upregulation of the glutamate-ammonia ligase (GLUL) gene in skeletal muscle, which is accompanied by altered glutamate/glutamine metabolism, setting them apart from other neurodegenerative disorders.

Abstract

The study conducted a comprehensive transcriptomic analysis of extraneural organs, including blood, spleen, and skeletal muscle, in mouse models of prion disease at different stages of progression. The key findings are:

Skeletal muscle showed the most consistent gene expression changes throughout the disease course, with two co-expression modules ("orange" and "darkgreen") exhibiting progressive upregulation and downregulation, respectively.

The glutamate-ammonia ligase (GLUL) gene was identified as a strong hub gene in the upregulated "orange" module and was consistently overexpressed in skeletal muscle of prion-infected mice across multiple prion strains (RML6, ME7, 22L).

The upregulation of GLUL was confirmed in skeletal muscle samples from patients with sporadic Creutzfeldt-Jakob disease (sCJD), both at the mRNA and protein levels.

The GLUL upregulation in prion diseases was not observed in other neurodegenerative disorders like Alzheimer's disease, dementia with Lewy bodies, or amyotrophic lateral sclerosis, suggesting it is a distinctive feature of prion diseases.

The GLUL upregulation was accompanied by reduced glutamate levels in skeletal muscle of prion-infected mice and sCJD patients, indicating a disruption in glutamate/glutamine metabolism 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, setting prion diseases apart from other neurodegenerative conditions.

Stats

Glutamate concentrations (nmol/mg) in skeletal muscle lysates of mice inoculated with prion strains RML6, ME7, and 22L were reduced at the terminal stage of the disease.
Glutamine concentrations (nmol/mg) in skeletal muscle lysates of mice inoculated with prion strains RML6, ME7, and 22L were unchanged across disease progression.
Glutamate concentrations (nmol/mg) in skeletal muscle lysates of sCJD patients were reduced compared to non-sCJD controls.
Glutamine concentrations (nmol/mg) in skeletal muscle lysates of sCJD patients were unchanged compared to non-sCJD controls.

Quotes

"Prions can be present in the blood, where they bind to plasminogen (4). Blood is a documented route of infection and remains a challenge for transfusion medicine (5, 6)."
"Skeletal muscles of patients with acquired and sporadic CJD show PrPSc deposits in peripheral nerve fibers (10). Thus, while the most visible toxicity of prion diseases (PrDs) occurs in the brain, there is increasing evidence of peripheral manifestations which may be relevant to disease symptoms."
"Glutamate-ammonia ligase (GLUL) is uniquely upregulated in skeletal muscle of prion-infected mice and humans, but not in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), or dementia with Lewy bodies (DLB)."

Key Insights Distilled From

Prion diseases disrupt the glutamate/glutamine metabolism in skeletal muscle

by Caredio,D., ... at www.biorxiv.org 11-02-2023

https://www.biorxiv.org/content/10.1101/2023.10.31.564879v2

Deeper Inquiries

How might the upregulation of GLUL in skeletal muscle influence the progression and clinical manifestations of prion diseases?

The upregulation of GLUL in skeletal muscle during prion diseases can have significant implications for disease progression and clinical manifestations. GLUL, also known as glutamate-ammonia ligase, plays a crucial role in catalyzing the conversion of glutamate to glutamine. This upregulation leads to an imbalance in glutamate and glutamine levels in skeletal muscle, which can impact various metabolic processes and signaling pathways.
One potential consequence of GLUL upregulation is the disruption of glutamate/glutamine metabolism in skeletal muscle. This imbalance can affect energy production, neurotransmission, and cellular signaling, all of which are essential for normal muscle function. Additionally, altered glutamate and glutamine levels can impact protein synthesis, cell growth, and overall muscle health.
Furthermore, the dysregulation of glutamate/glutamine metabolism in skeletal muscle may contribute to the systemic spread of prions throughout the body. Prions can accumulate in extraneural tissues, including skeletal muscle, and the upregulation of GLUL in these tissues may facilitate the replication and spread of prions. This could potentially exacerbate disease progression and lead to more severe clinical manifestations.
Overall, the upregulation of GLUL in skeletal muscle in prion diseases can have a cascading effect on various metabolic pathways, cellular functions, and disease processes, ultimately influencing the progression and clinical outcomes of the disease.

What are the potential mechanisms underlying the specific GLUL upregulation in prion diseases compared to other neurodegenerative disorders?

The specific upregulation of GLUL in prion diseases compared to other neurodegenerative disorders may be attributed to the unique pathophysiological mechanisms underlying prion infections. Several potential mechanisms could explain this specificity:

Prion Strain Variability: Different prion strains exhibit distinct biological properties, including tissue tropism and neuropathological features. The consistent upregulation of GLUL across various prion strains suggests that this phenomenon is a common feature of prion diseases, possibly driven by strain-specific interactions with host tissues.

Peripheral Manifestations: Prions can accumulate in extraneural organs, such as skeletal muscle, spleen, and blood. The presence of prions in skeletal muscle may trigger specific molecular responses, including the upregulation of GLUL, which are unique to prion diseases and not observed in other neurodegenerative disorders.

Metabolic Dysregulation: Prion diseases are associated with alterations in metabolism, including disruptions in glutamate/glutamine metabolism. The upregulation of GLUL in skeletal muscle may be a compensatory response to maintain glutamine levels in the face of prion-induced metabolic changes, highlighting the specificity of this dysregulation to prion diseases.

Disease-Specific Pathways: Prion diseases involve the misfolding and aggregation of prion proteins, leading to neurodegeneration and systemic pathology. The specific molecular pathways and cellular responses triggered by prions may differ from those in other neurodegenerative disorders, resulting in unique patterns of gene expression, including the upregulation of GLUL.

In summary, the specific upregulation of GLUL in prion diseases compared to other neurodegenerative disorders may stem from a combination of strain variability, peripheral manifestations, metabolic dysregulation, and disease-specific pathophysiology.

Could targeting the disrupted glutamate/glutamine metabolism in skeletal muscle be a viable therapeutic approach for prion diseases?

Targeting the disrupted glutamate/glutamine metabolism in skeletal muscle could indeed be a promising therapeutic approach for prion diseases. The dysregulation of glutamate and glutamine levels, along with the upregulation of GLUL, plays a significant role in the pathophysiology of prion diseases. By addressing these metabolic imbalances, it may be possible to modulate disease progression and improve clinical outcomes.
Here are some potential strategies for targeting disrupted glutamate/glutamine metabolism in skeletal muscle:

GLUL Inhibition: Developing inhibitors targeting GLUL activity could help normalize glutamate and glutamine levels in skeletal muscle. By reducing the overproduction of glutamine, these inhibitors may mitigate the metabolic dysregulation associated with prion diseases.

Metabolic Modulators: Small molecules or compounds that regulate glutamate and glutamine metabolism could be explored as potential therapeutics. These modulators could restore the balance of these metabolites in skeletal muscle and potentially slow down disease progression.

Nutritional Interventions: Dietary interventions aimed at optimizing glutamate and glutamine levels in skeletal muscle could be beneficial. Nutritional strategies that promote a healthy balance of amino acids and metabolic substrates may support muscle function and mitigate the effects of prion-induced metabolic changes.

Gene Therapy: Targeted gene therapy approaches could be used to modulate the expression of genes involved in glutamate/glutamine metabolism in skeletal muscle. By regulating the expression of key metabolic enzymes, such as GLUL, it may be possible to restore metabolic homeostasis and improve muscle function.

Overall, targeting the disrupted glutamate/glutamine metabolism in skeletal muscle represents a novel and potentially effective therapeutic strategy for prion diseases. Further research and preclinical studies are needed to explore the feasibility and efficacy of these approaches in treating prion-related metabolic dysregulation and associated clinical manifestations.