Brain glycogen serves as a critical glucosamine cache required for protein glycosylation

Glycosylation defects are a hallmark of many nervous system diseases. However, the molecular and metabolic basis for this pathology are not fully understood. In this study, we found that N‐linked protein glycosylation in the brain is coupled to glucosamine metabolism through glycogenolysis. We discovered that glucosamine is an abundant constituent of brain glycogen, which functions as a glucosamine reservoir for glycosylation precursors. We defined the incorporation of glucosamine into glycogen by glycogen synthase and release by glycogen phosphorylase in vitro by biochemical and structural methodologies, in situ in primary astrocytes, and in vivo by isotopic tracing and mass spectrometry. Using mouse models of two glycogen storage diseases, we showed that disruption of brain glycogen metabolism causes global decreases in free UDP‐N‐acetyl‐glucosamine and N‐linked protein glycosylation. These findings revealed key fundamental biological role for brain glycogen in protein glycosylation with direct relevance to multiple human diseases of the central nervous system.