Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore.
J Cell Physiol. 2020 Nov;235(11):7653-7662. doi: 10.1002/jcp.29682. Epub 2020 Apr 2.
Prolonged survival of a typical postmitotic neuron hinges on a balance between multiple processes, among these are a sustenance of ATP production and protection against reactive oxygen species. In neuropathological conditions, mitochondrial defects often lead to both a drop in ATP levels, as well as increase reactive oxygen species production from inefficient electron transport processes and NADPH-oxidases activities. The former often resulted in the phenomenon of compensatory aerobic glycolysis. The latter stretches the capacity of the cell's redox buffering capacity, and may lead to damages of key enzymes involved in energy metabolism. Several recent reports have indicated that enhancing glucose availability and uptake, as well as increasing glycolytic flux via pharmacological or genetic manipulation of glycolytic enzymes, could be protective in animal models of several major neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Activation of canonical Wnt signaling, which improves disease symptoms in mouse models of Alzheimer's disease also appears to work via an elevation of glycolytic enzymes and enhance glucose metabolism. Here, I discuss these findings and the possible underlying mechanisms of how an increase in glucose uptake and glycolysis could be neuroprotective. Increased glycolytic production of ATP would help alleviate energy deficiency, and ATP's hydrotropic effect may enhance solubility and clearance of toxic aggregates prevalent in many neurodegenerative diseases. Furthermore, channeling of glucose into the Pentose Phosphate Pathway would increase the redox buffering capacity of the cell.
典型的有丝分裂后神经元的长期存活取决于多种过程之间的平衡，其中包括维持 ATP 产生和防止活性氧物质的产生。在神经病理学条件下，线粒体缺陷通常导致 ATP 水平下降，以及电子传递过程和 NADPH 氧化酶活性效率低下导致活性氧物质产生增加。前者通常导致补偿性需氧糖酵解现象。后者超出了细胞氧化还原缓冲能力的承受能力，并可能导致参与能量代谢的关键酶受损。最近有几项报告表明，通过药理学或遗传手段对糖酵解酶进行操作，增加葡萄糖的可用性和摄取，以及增加糖酵解通量，可能对几种主要神经退行性疾病（包括帕金森病、亨廷顿病和肌萎缩性侧索硬化症）的动物模型具有保护作用。经典 Wnt 信号通路的激活，通过提高阿尔茨海默病小鼠模型中的糖酵解酶和增强葡萄糖代谢，也似乎具有保护作用。在这里，我讨论了这些发现以及葡萄糖摄取和糖酵解增加可能具有神经保护作用的潜在机制。增加糖酵解产生的 ATP 将有助于缓解能量缺乏，并且 ATP 的亲水性效应可能会增强许多神经退行性疾病中普遍存在的有毒聚集体的溶解度和清除。此外，将葡萄糖导入戊糖磷酸途径将增加细胞的氧化还原缓冲能力。
