The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Nat Commun. 2024 Jun 19;15(1):5206. doi: 10.1038/s41467-024-49256-3.
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.
葡萄糖代谢和蛋白质错误折叠是包括帕金森病在内的与年龄相关的神经退行性疾病的关键特征，但它们的机制联系在很大程度上尚未被探索。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-糖基化合成速率降低。葡萄糖通量的受损是通过未折叠蛋白反应和己糖胺途径之间信号的破坏，选择性降低限速酶 GFPT2 来实现的。未折叠蛋白反应的失败和 N-糖基化的减少导致不成熟的溶酶体水解酶错误折叠和积累，而通过己糖胺途径加速葡萄糖通量则可以挽救水解酶的功能并减少病理性α-突触核蛋白。我们的数据表明，己糖胺途径将葡萄糖代谢与溶酶体活性整合在一起，而其在帕金森病中的失败是通过未折叠蛋白反应-己糖胺途径轴的解耦联引起的。这些发现为通过己糖胺途径增强来恢复蛋白质稳定性提供了新的方法。
