Protein glycosylation and synaptic transmission: brain glycogen keeps them separated

Abstract Brain glycogen has for long been regarded uniquely as a source of energetic support in situations of emergency or heightened activity. Recently, brain glycogen was found to contain a significant amount of glucosamine, which is used to sustain protein glycosylation. In this update, we highlight that glucosamine synthesis through the hexosamine pathway would subtract glutamine, which is instead indispensable for glutamate and GABA recycling. Brain glycogen seems then to serve an additional role. By providing glucosamine and, through it, inhibiting the hexosamine pathway, glycogen avoids glutamine depletion. In neurological glycogen storage diseases, the short-circuit between the hexosamine pathway and neurotransmitters recycling can cause epileptic seizures, which are the most common acute manifestation in these pathologies. We finally discuss the metabolic and symptomatic superposition of glycogen storage diseases with congenital disorders of glycosylation, concluding that treatments ameliorating the clinical symptoms in some of the discussed pathologies could also be beneficial in the others.