星形胶质细胞中连接蛋白43在肌萎缩侧索硬化中促发运动神经元毒性

Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateralsclerosis

肌萎缩侧索硬化(ALS)是一种神经退行性疾病,其特征是中枢神经系统中运动神经元的进行性丧失。星形胶质细胞在ALS的疾病进程中起重要作用。星形胶质细胞通过缝隙连接蛋白家族,如连接蛋白(Connexin,Cx)互相连接。Cx43是中枢神经系统中保持稳态的主要星形胶质细胞连接蛋白。在病理状态下,连接蛋白的表达和功能发生改变。本文发现,在ALS中Cx43异常增高是星形胶质细胞介导的毒性作用机制之一。笔者观察到,在ALS SOD1^(G93A)小鼠模型的疾病进程中,Cx43表达进行性增高。尤其是,在ALS患者的运动皮质和脊髓也能检测到Cx43增高。从SOD1^(G93A)小鼠中分离的星形胶质细胞,与人诱导多能干细胞衍生的星形胶质细胞一样,都检测到Cx43蛋白增高,且为独立于神经元共培养的内源性现象。与对照的星形胶质细胞过表达的野生型SOD1(SOD1^(WT))相比,SOD1^(G93A)星形胶质细胞中增高的Cx43表达可产生重要的功能性影响。本文发现,SOD1^(G93A)星形胶质细胞表现出缝隙连接偶联增强,半通道介导活动升高,细胞内钙离子水平上升。最后,本文检测Cx43蛋白表达升高对MN生存的影响,发现应用pan-Cx43阻滞剂和Cx43半通道阻滞剂均对与SOD1^(G93A)星形胶质细胞共培养的MNs有神经保护作用。这些新发现展示出未被认知的Cx43在ALS相关的运动神经元丢失中所起作用。

Amyotrophic lateral sclerosis （ALS） is a neurodegenerative disease characterized by progressive loss of motor neurons in the CNS. Astrocytes play a critical role in disease progression ofALS. Astrocytes are intercon- nected through a family of gap junction proteins known as connexins （Cx）. Cx43 is a major astrocyte connexin conducting crucial homeostatic functions in the CNS. Under pathological conditions, connexin expression and functions are altered. Here we report that an abnormal increase in Cx43 expression serves as one of the mecha- nisms for astrocyte-mediated toxicity in ALS. We observed a progressive increase in Cx43 expression in the SOD 1G93A mouse model of ALS during the disease course. Notably, this increase in Cx43 was also detected in the motor cortex and spinal cord of ALS patients. Astrocytes isolated from SOD 1G93A mice as well as human induced pluripotent stem cell （iPSC）-derived astrocytes showed an increase in Cx43 protein, which was found to be an en- dogenous phenomenon independent of neuronal co-culture.