Liu Chong, Li Dongxiao, Lv Cui, Gao Zhisong, Qi Yinkuang, Wu Hongran, Tian Yunyun, Guo Yansu
Beijing Geriatric Healthcare Center, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xicheng, Beijing 100053, China; Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
Neuroscience. 2020 Apr 15;432:84-93. doi: 10.1016/j.neuroscience.2020.02.034. Epub 2020 Feb 28.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron loss and gliosis in the spinal cord, brain stem and cortex. The Notch signaling pathway has been reported to be dysfunctional in neurodegenerative diseases, including ALS. However, the exact mechanism is still unclear. Here, we detected Notch signaling activation in proliferating glial cells, Notch inactivation in motor neurons in the spinal cord of the SOD1-G93A model, and dramatic changes of cellular relocalization of Notch pathway signaling molecules, including activated Notch intracellular domain (NICD), Notch ligands (Jagged1 and DLL4) and the target gene Hes1. We found that Notch activation was universal in proliferating astrocytes and that the Notch ligand Jagged1 was uniquely upregulated in proliferating microglia, while DLL4 expression was increased in both activated astrocytes and degenerating oligodendrocytes. Our results indicate that microglia may play an important role in the intercellular receptor-ligand interaction of the Notch signaling pathway and contribute to the pathogenesis of motor neuron loss in ALS mice. Further experiments are required to clarify the exact mechanism responsible for Notch dysfunction in ALS.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是脊髓、脑干和皮质中的运动神经元丧失和胶质细胞增生。据报道，Notch信号通路在包括ALS在内的神经退行性疾病中功能失调。然而，确切机制仍不清楚。在这里，我们检测到在增殖的胶质细胞中Notch信号激活，在SOD1-G93A模型脊髓中的运动神经元中Notch失活，以及Notch通路信号分子的细胞重新定位发生显著变化，包括活化的Notch胞内结构域（NICD）、Notch配体（Jagged1和DLL4）和靶基因Hes1。我们发现Notch激活在增殖的星形胶质细胞中普遍存在，并且Notch配体Jagged1在增殖的小胶质细胞中独特地上调，而DLL4表达在活化的星形胶质细胞和退化的少突胶质细胞中均增加。我们的结果表明，小胶质细胞可能在Notch信号通路的细胞间受体-配体相互作用中起重要作用，并有助于ALS小鼠运动神经元丧失的发病机制。需要进一步的实验来阐明ALS中Notch功能障碍的确切机制。
