PDF(Pubmed)
Abstract：
Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson\'s disease, however their mechanistic linkage is largely unexplored. The hexosamine biosynthetic pathway utilizes glucose and uridine-5\'-triphosphate to generate N-linked glycans required for protein folding in the endoplasmic reticulum. Here we find that Parkinson\'s patient midbrain cultures accumulate glucose and uridine-5\'-triphosphate, while N-glycan synthesis rates are reduced. Impaired glucose flux occurred by selective reduction of the rate-limiting enzyme, GFPT2, through disrupted signaling between the unfolded protein response and the hexosamine pathway. Failure of the unfolded protein response and reduced N-glycosylation caused immature lysosomal hydrolases to misfold and accumulate, while accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein. Our data indicate that the hexosamine pathway integrates glucose metabolism with lysosomal activity, and its failure in Parkinson\'s disease occurs by uncoupling of the unfolded protein response-hexosamine pathway axis. These findings offer new methods to restore proteostasis by hexosamine pathway enhancement.
摘要：
葡萄糖代谢紊乱和蛋白质错误折叠是年龄相关性神经退行性疾病（包括帕金森病）的关键特征。然而，它们的机械联系在很大程度上是未经探索的。己糖胺生物合成途径利用葡萄糖和尿苷-5'-三磷酸生成内质网中蛋白质折叠所需的N-连接聚糖。在这里，我们发现帕金森病患者的中脑培养物积累葡萄糖和尿苷-5'-三磷酸，而N-聚糖合成速率降低。限速酶的选择性还原导致葡萄糖通量受损，GFPT2，通过破坏未折叠蛋白反应和己糖胺途径之间的信号传导。未折叠蛋白反应失败和N-糖基化减少导致未成熟溶酶体水解酶错误折叠和积累，在加速通过己糖胺途径的葡萄糖通量的同时，挽救了水解酶的功能并减少了病理性α-突触核蛋白。我们的数据表明，己糖胺途径整合了葡萄糖代谢与溶酶体活性，其在帕金森病中的失败是通过解偶联未折叠的蛋白反应-己糖胺途径轴而发生的。这些发现提供了通过增强己糖胺途径来恢复蛋白稳定的新方法。
