The multifaceted roles of the brain glycogen

Abstract

Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non‐metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n‐GSDs). n‐GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late‐onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n‐GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.image

Preface: Special issue: 14thInternational Conference on Brain Energy Metabolism: Energy substrates and microbiome govern brain bioenergetics and cognitive function with aging

“…Matthew Gentry's exciting talk on “Emerging roles of brain glycogen and insights from neurological glycogen storage diseases” reported that glycogen‐derived glucosamine is a significant source of amino sugars required for protein glycosylation in the brain and that impairment of cerebral glycogen metabolism causes global decreases in free UDP‐N‐acetyl‐glucosamine and N‐linked protein glycosylation in two glycogen storage disease models. These novel findings identify a key new role for glycogen in brain function that is detailed in the review on “The multifaceted roles of brain glycogen” by Kia Markussen, Matt Gentry, and others (Markussen et al., 2023). Jordi Duran's talk focused on studies with animal models that demonstrate that neurons have an active glycogen metabolism that contributes to neuronal plasticity and tolerance to hypoxia, and showed how the accumulation of Lafora bodies in both astrocytes and neurons in Lafora Disease is responsible for the specific pathology of this neurodegenerative condition.…”