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

糖基化缺陷是许多神经系统疾病的标志。然而，这种病理学的分子和代谢基础尚不完全清楚。在这项研究中，我们发现大脑中的 N-连接蛋白糖基化通过糖原分解代谢引导至葡萄糖胺代谢。我们发现氨基葡萄糖是脑糖原的丰富成分，它可作为多种糖缀合物的氨基葡萄糖储库。我们证明了葡萄糖胺通过糖原合酶酶促掺入糖原，并通过生化和结构方法在原代星形胶质细胞和体内通过糖原磷酸化酶释放通过同位素示踪和质谱分析。使用两种糖原贮积病小鼠模型，我们发现脑糖原代谢的中断导致 UDP-N-乙酰氨基葡萄糖和 N-连接蛋白糖基化的游离池的全球减少。这些发现揭示了脑糖原在蛋白质糖基化中的基本生物学作用，与多种人类中枢神经系统疾病直接相关。