Edinburgh Medical School, University of Edinburgh, Edinburgh EH16 4TJ, U.K.
UK Dementia Research Institute at The University of Edinburgh, Edinburgh EH16 4TJ, U.K.
Biochem Soc Trans. 2017 Dec 15;45(6):1295-1303. doi: 10.1042/BST20170013. Epub 2017 Nov 17.
Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory.
多种神经退行性疾病在病理学上具有一些共同特征,许多疾病都表现出对大脑众多内稳态过程的破坏。因此,失衡的炎症状态、谷氨酸代谢失调、代谢低下和氧化应激与许多疾病有关。这些病理过程可以在上下游相互影响,使得情况变得复杂,但这也意味着成功靶向一个区域可能会对其他区域产生影响。这种靶向治疗需要了解在健康状态下内稳态是如何维持的,以便发现增强疾病内稳态的策略。一个恰当的例子是氧化还原稳态,它由转录因子 Nrf2 协调调节的抗氧化防御机制维持,不仅可以防止氧化应激,还可以防止神经退行性疾病模型中的炎症和神经元丢失。在大脑中控制炎症、线粒体生物发生、谷氨酸摄取和能量代谢的其他内稳态过程的主要调节因子的出现提出了一个问题,即它们是否也可以被靶向以改变疾病轨迹。