Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.

中文翻译：

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肌萎缩性侧索硬化症中枢神经系统葡萄糖代谢：治疗靶点吗？

肌萎缩性侧索硬化症（ALS）是一种致命的进行性神经退行性疾病，其主要特征是大脑中上运动神经元和脑干和脊髓中下运动神经元的选择性变性。神经元选择性死亡的确切机制尚不清楚。越来越多的证据表明，动物模型和ALS患者的细胞和全身能量代谢异常。许多ALS患者表现出代谢变化，例如代谢亢进和体重减轻。尽管在ALS患者中观察到了这些全身代谢变化，但是代谢失调的起源仍有待充分阐明。许多临床前研究表明，在细胞水平上潜在的生物能损伤可能会导致ALS的代谢功能障碍。特别地，中枢神经系统葡萄糖转运和代谢中的缺陷似乎导致线粒体能量生成减少和氧化应激增加，这似乎有助于ALS的疾病发展。在这里，我们回顾了有关ALS中CNS葡萄糖代谢功能障碍的当前知识和理解，重点是葡萄糖转运，糖酵解，戊糖磷酸途径，TCA循环和氧化磷酸化的代谢损伤。我们还总结了糖原代谢和神经胶质代谢相互作用中发现的障碍。最后，我们讨论了有关如何修改代谢障碍以减缓ALS疾病进展的未来研究的选择。