Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations.
Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations.
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DOI：
10.1084/jem.20161673
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发表时间：
2017-03-06
期刊：
影响因子：
--
通讯作者：
Bading H
中科院分区：
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作者：
Bading H
Bding综述了许多神经退行性疾病，这些疾病表现为突触外NMDA受体信号增强，导致线粒体功能障碍、转录失控以及树突结构和连通性丧失的病理性三联症。定义了治疗对象的区域，以指导新型神经保护性组合疗法的设计。突触外N-甲基-d-天冬氨酸(NMDA)受体的激活会导致神经变性和细胞死亡。该病的发病机制包括线粒体功能障碍，神经元结构和连接的完整性丧失，以及CREB(环磷酸腺苷反应元件结合蛋白)关闭和IIa类组蛋白脱乙酰基酶的核积聚导致的激发-转录偶联中断。三联体内部的相互依赖加剧了疾病的加速发展，最终导致线粒体能量产生失败和细胞丢失。急性和缓慢进展的神经退行性疾病，包括中风、阿尔茨海默病、肌萎缩侧索硬化症和亨廷顿病，都有共同的死亡信号，由突触外NMDA受体引起的死亡信号增加，原因是细胞外谷氨酸浓度升高或NMDA受体重新定位到突触外部位。定义了治疗目标的六个领域，在此基础上提出了一种广泛适用的联合治疗方法，以对抗突触外NMDA受体信号的病理性三联体，这种信号在许多神经退行性疾病中很常见。
Bading reviews many neurodegenerative diseases sharing heightened extrasynaptic NMDA receptor signaling, which causes a pathological triad with mitochondrial dysfunction, deregulation of transcription, and loss of dendritic structures and connectivity. Areas of therapeutic objects are defined to guide the design of novel neuroprotective combination therapies. Activation of extrasynaptic N-methyl-d-aspartate (NMDA) receptors causes neurodegeneration and cell death. The disease mechanism involves a pathological triad consisting of mitochondrial dysfunction, loss of integrity of neuronal structures and connectivity, and disruption of excitation–transcription coupling caused by CREB (cyclic adenosine monophosphate–responsive element-binding protein) shut-off and nuclear accumulation of class IIa histone deacetylases. Interdependency within the triad fuels an accelerating disease progression that culminates in failure of mitochondrial energy production and cell loss. Both acute and slowly progressive neurodegenerative conditions, including stroke, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, share increased death signaling by extrasynaptic NMDA receptors caused by elevated extracellular glutamate concentrations or relocalization of NMDA receptors to extrasynaptic sites. Six areas of therapeutic objectives are defined, based on which a broadly applicable combination therapy is proposed to combat the pathological triad of extrasynaptic NMDA receptor signaling that is common to many neurodegenerative diseases.