[Roles of metabolic compartmentalization by astrocytes and neurons in the pathophysiology and treatment of Parkinson's disease].
[Roles of metabolic compartmentalization by astrocytes and neurons in the pathophysiology and treatment of Parkinson's disease].
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发表时间：
2013-12
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通讯作者：
Shinichi Takahashi;Morinobu Seki;N. Suzuki
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作者：
Shinichi Takahashi;Morinobu Seki;N. Suzuki
线粒体功能障碍与特发性和家族性帕金森病（PD）的发病机制有关。黑质中的多巴胺神经元表现出自主的起搏活动，以维持纹状体中最佳的多巴胺浓度，从而激活能量代谢。神经元细胞中ATP的产生依赖于线粒体葡萄糖氧化，而与神经元激活相关的活性氧（ROS）的产生可能是多巴胺神经元线粒体损伤的主要原因。α -突触核蛋白是路易小体的主要成分，可诱导线粒体损伤，几个负责家族性PD的基因编码正常线粒体功能所需的分子。此外，多巴胺的自氧化产生多巴胺醌和ROS。星形胶质细胞通过糖酵解作用向神经元提供葡萄糖产生的乳酸。星形胶质细胞中糖酵解的分流途径戊糖-磷酸途径（PPP）的共激活在保护神经元对抗ROS与谷胱甘肽过氧化物酶和谷胱甘肽（GSH）的还原形式中起着关键作用。除了与糖酵解激活相关的PPP的变构调节外，星形胶质细胞中的PPP还可以通过kelch样烯酰辅酶a水合酶相关蛋白1 (Keap1)/核因子-红细胞2 p45亚单位相关因子2 （Nrf2）系统被ROS激活。PPP的限速酶葡萄糖-6-磷酸脱氢酶（G6PDH）受Keap1/Nrf2系统的转录调控，该系统是2期解毒酶的主要调控因子。ROS被认为可以修饰Keap1的巯基残基，并促进Nrf2与Keap1的分离。随后，Nrf2转位到细胞核中，诱导G6PDH的转录。星形胶质细胞中Keap1/Nrf2 PPP的药理激活可能为预防PD的发生和发展提供一种新的策略。
Mitochondrial dysfunction has been implicated in the pathogenesis of both idiopathic and familial Parkinson's disease (PD). Dopamine neurons in the substantia nigra exhibit autonomous pacemaking activity to maintain an optimal dopamine concentration in the striatum, resulting in the activation of energy metabolism. ATP production in neuronal cells is dependent on mitochondrial glucose oxidation, and reactive oxygen species (ROS) production associated with neuronal activation might be a major cause of mitochondrial damage in dopamine neurons. Alpha-synuclein, a major component of Lewy bodies, induces mitochondrial damage, and several genes responsible for familial PD encode molecules necessary for normal mitochondrial function. In addition, the auto-oxidation of dopamine produces dopamine quoinone and ROS. Astroglia provide neurons with lactate produced from glucose via glycolysis in response to neuronal activation. The co-activation of the pentose-phosphate pathway (PPP), a shunt pathway of glycolysis, in astroglia plays a pivotal role in protecting neurons against ROS with glutathione peroxidase and the reduced form of glutathione (GSH). In addition to the allosteric regulation of the PPP, which is associated with the activation of glycolysis, the PPP in astroglia can also be activated by ROS through the Kelch-like enoyl-CoA hydratase-associated protein 1 (Keap1)/nuclear factor-erythroid 2 p45 subunit-related factor 2 (Nrf2) system. A rate-limiting enzyme of the PPP, glucose-6-phosphate dehydrogenase (G6PDH), is transcriptionally regulated by the Keap1/Nrf2 system, which is a master regulator of phase 2 detoxifying enzymes. ROS is thought to modify the thiol residue of Keap1 and to facilitate Nrf2 dissociation from Keap1. Thereafter, Nrf2 translocates into the nucleus where it induces the transcription of G6PDH. The pharmacological activation of the Keap1/Nrf2 PPP in astroglia may provide a novel strategy for preventing the onset and progression of PD.