Knockdown of SMN by RNA interference induces apoptosis in differentiated P19 neural stem cells
Knockdown of SMN by RNA interference induces apoptosis in differentiated P19 neural stem cells
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DOI：
10.1016/j.brainres.2007.09.025
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发表时间：
2007-12-05
期刊：
影响因子：
2.9
通讯作者：
Wood, Matthew
中科院分区：
文献类型：
--
作者：
Trulzsch, Barbara;Garnett, Catherine;Wood, Matthew
脊髓性肌萎缩症（SMA）是一种常见的神经退行性疾病，由运动神经元存活基因（SMN）突变引起，导致受影响个体的SMN蛋白水平降低。在SMA中，运动神经元选择性地退化，然而，细胞死亡的机制以及SMN在该过程中的确切作用尚不完全清楚。在这项研究中，我们应用RNA干扰（RNAi）敲低Smn基因表达的小鼠胚胎癌干细胞系P19，它可以分化为神经元细胞。Smn损失对分化的P19神经元细胞的凋亡细胞死亡的直接影响，并在较小程度上在未分化的细胞中观察到。细胞凋亡可以通过SMN拯救结构的表达部分逆转，通过加入半胱天冬酶抑制剂ZVAD-favorite是可逆的，并涉及细胞色素c途径。这项研究首次表明，SMN的敲低导致哺乳动物神经元细胞的凋亡，并对理解SMA运动神经元特异性细胞丢失的原因和确定这种疾病的新治疗靶点具有意义。(c)2007 Elsevier B. V.保留所有权利。
Spinal muscular atrophy (SMA) is a common neurodegenerative disease that is caused by mutations in the survival of motor neuron gene (SMN), leading to reduced levels of the SMN protein in affected individuals. in SMA, motor neurons selectively degenerate, however, the mechanism of cell death and the precise role of SMN in this process are not completely understood. In this study, we apply RNA interference (RNAi) to knockdown Smn gene expression in the murine embryonal carcinoma stem cell line P19, which can be differentiated into neuronal cells. A direct effect of Smn loss on apoptotic cell death in differentiated P19 neuronal cells, and to a lesser extent in undifferentiated cells was observed. Apoptosis could be partly reversed by expression of an SMN rescue construct, was reversible by the addition of the caspase-inhibitor ZVAD-fmk and involved the cytochrome c pathway. This study shows for the first time that knockdown of SMN results in apoptosis in mammalian neuronal cells and has implications for understanding the cause of motor neuron-specific cell loss in SMA, and for identifying novel therapeutic targets for this disease. (c) 2007 Elsevier B.V. All rights reserved.