Glycogen Metabolism in Neurodegenerative Disorders

Glycogen serves as an essential energy reserve in the central nervous system, predominantly stored in astrocytes but also synthesised at low levels in neurons. Its synthesis is driven by glycogen synthase and regulated through branching enzymes, while degradation relies on glycogen phosphorylase. A finely tuned balance of phosphorylation and dephosphorylation, mediated by enzymes such as laforin (a dual specificity phosphatase) and malin (an E3 ubiquitin ligase), ensures normal glycogen architecture and solubility. In several neurodegenerative disorders, most notably Lafora disease, mutations in the genes encoding laforin or malin disrupt this balance, leading to poorly branched, hyperphosphorylated glycogen that aggregates into insoluble polyglucosan inclusions called Lafora bodies. These deposits provoke neuronal dysfunction, synaptic failure and progressive cell loss. Beyond this rare genetic epilepsy, aberrant glycogen accumulation and related polysaccharide bodies also emerge in the ageing brain and in conditions such as Alzheimer’s and Parkinson’s diseases, implicating dysregulated glycogen metabolism in wider neurodegenerative processes. Research has begun to reveal crosstalk between glycogen structural regulators, protein quality control pathways (including autophagy) and neuronal survival, highlighting potential avenues for disease-modifying therapies that restore normal glycogen turnover and prevent toxic inclusions.

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Glycogen Metabolism in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in glycogen metabolism in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Glycogen: Branched polymer of glucose that serves as an intracellular energy store.

Glycogen synthase: Enzyme that catalyses the addition of glucose units to growing glycogen chains.

Glycogen phosphorylase: Enzyme responsible for releasing glucose-1-phosphate from glycogen during degradation.

Laforin: Dual specificity phosphatase that removes covalent phosphate groups from glycogen.

Malin: E3 ubiquitin ligase that partners with laforin to regulate glycogen metabolism.

Lafora bodies: Insoluble, poorly branched polyglucosan inclusions characteristic of Lafora disease.

References

1. Lafora disease offers a unique window into neuronal glycogen metabolism. Journal of Biological Chemistry (2018).
2. Laforin, a Dual Specificity Phosphatase That Dephosphorylates Complex Carbohydrates*. Journal of Biological Chemistry (2006).
3. Genetic Depletion of the Malin E3 Ubiquitin Ligase in Mice Leads to Lafora Bodies and the Accumulation of Insoluble Laforin*. Journal of Biological Chemistry (2010).
4. Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan. International Journal of Molecular Sciences (2017).
5. Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease*. Journal of Biological Chemistry (2008).
6. Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease. EMBO Molecular Medicine (2011).
7. Neuronal glycogen synthesis contributes to physiological aging. Aging Cell (2014).
8. Lafora Disease: A Ubiquitination-Related Pathology. Cells (2018).
9. PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease. PLOS Genetics (2011).
10. Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease. EMBO Molecular Medicine (2017).
11. Natural history of Lafora disease: a prognostic systematic review and individual participant data meta-analysis. Orphanet Journal of Rare Diseases (2021).