Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis.
Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis.
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作者：
Almad AA;Doreswamy A;Gross SK;Richard JP;Huo Y;Haughey N;Maragakis NJ
肌萎缩侧索硬化症（ALS）是一种以中枢神经系统运动神经元进行性丧失为特征的神经退行性疾病。星形胶质细胞在ALS的疾病进展中起关键作用。星形胶质细胞通过称为连接蛋白（Cx）的间隙连接蛋白家族相互连接。Cx43是一种主要的星形胶质细胞连接蛋白，在中枢神经系统中发挥重要的稳态功能。在病理条件下，连接蛋白的表达和功能被改变。在这里，我们报告说，Cx43表达的异常增加作为星形胶质细胞介导的ALS毒性的机制之一。我们观察到Cx43的表达进行性增加的SOD1G93A小鼠模型的ALS在病程中。值得注意的是，在ALS患者的运动皮层和脊髓中也检测到Cx43的这种增加。从SOD1G93A小鼠分离的星形胶质细胞以及人诱导多能干细胞（iPSC）衍生的星形胶质细胞显示Cx43蛋白的增加，这被发现是独立于神经元共培养的内源性现象。与过表达野生型SOD1（SOD1WT）的对照星形胶质细胞相比，在SOD1G93A星形胶质细胞中检测时，Cx43表达增加导致重要的功能后果。我们观察到SOD1G93A星形胶质细胞表现出增强的间隙连接偶联，增加半通道介导的活性，和升高的细胞内钙水平。最后，我们测试了Cx43表达增加对MN存活的影响，并观察到使用泛Cx43阻断剂和Cx43半通道阻断剂对与SOD1G93A星形胶质细胞一起培养的MN赋予神经保护作用。这些新的发现表明Cx43在ALS相关运动神经元丢失中的作用以前未被认识。
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 of ALS. Astrocytes are interconnected 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 mechanisms for astrocyte-mediated toxicity in ALS. We observed a progressive increase in Cx43 expression in the SOD1G93A 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 SOD1G93A mice as well as human induced pluripotent stem cell (iPSC)-derived astrocytes showed an increase in Cx43 protein, which was found to be an endogenous phenomenon independent of neuronal co-culture. Increased Cx43 expression led to important functional consequences when tested in SOD1G93A astrocytes when compared to control astrocytes over-expressing wild-type SOD1 (SOD1WT). We observed SOD1G93A astrocytes exhibited enhanced gap junction coupling, increased hemichannel-mediated activity, and elevated intracellular calcium levels. Finally, we tested the impact of increased expression of Cx43 on MN survival and observed that use of both a pan Cx43 blocker and Cx43 hemichannel blocker conferred neuroprotection to MNs cultured with SOD1G93A astrocytes. These novel findings show a previously unrecognized role of Cx43 in ALS-related motor neuron loss.
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影响因子：
9.3
作者：
Cui Y;Masaki K;Yamasaki R;Imamura S;Suzuki SO;Hayashi S;Sato S;Nagara Y;Kawamura MF;Kira J
通讯作者：
Kira J
DOI：
10.1186/1478-811x-7-4
发表时间：
2009-03-12
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Dbouk HA;Mroue RM;El-Sabban ME;Talhouk RS
通讯作者：
Talhouk RS
影响因子：
5.3
作者：
Keller, A. Florence;Gravel, Mathieu;Kriz, Jasna
通讯作者：
Kriz, Jasna
影响因子：
3.5
作者：
Froger, Nicolas;Orellana, Juan A.;Giaume, Christian
通讯作者：
Giaume, Christian
影响因子：
5.3
作者：
Kawamata, Hibiki;Manfredi, Giovanni
通讯作者：
Manfredi, Giovanni