The JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death
The JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death
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DOI：
10.1007/s11010-012-1465-x
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发表时间：
2013-01-01
影响因子：
4.3
通讯作者：
Matsuoka, Masaaki
中科院分区：
文献类型：
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作者：
Suzuki, Hiroaki;Matsuoka, Masaaki
交互反应dna结合蛋白43 （TDP-43）的失调与肌萎缩性侧索硬化症（ALS）和泛素阳性包涵体（FTLD-U）额颞叶变性的发病机制密切相关。在ALS和FTLD-U患者中，TDP-43表达水平升高，这一观察结果有力地证明了TDP-43表达上调在发病机制中的作用。我们之前发现TDP-43低级别（2 - 5倍于内源性水平）过表达通过上调Bim和CHOP表达，下调Bcl-xL表达诱导神经元细胞死亡。在本研究中，我们进一步发现TDP-43的低级别过表达增加了磷酸化的c-Jun n -末端激酶（JNK）的水平，并且与JNK抑制剂、显性阴性JNK的表达或显性阴性c-Jun的表达共孵育可抑制TDP-43诱导的NSC34运动神经元细胞死亡。这些数据共同提示JNK/c-Jun信号轴参与了tdp -43诱导的细胞死亡。
Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The contribution of the upregulation of TDP-43 expression to the pathogenesis has been strongly suggested by the observation that the level of TDP-43 expression is increased in both ALS and FTLD-U patients. We previously found that the low-grade (twice to five times more than the endogenous level) overexpression of TDP-43 induces neuronal cell death through the upregulation of Bim and CHOP expression and the downregulation of Bcl-xL expression. In this study, we further show that the low-grade overexpression of TDP-43 increases the level of phosphorylated c-Jun N-terminal kinase (JNK) and the co-incubation with a JNK inhibitor, the expression of a dominant-negative JNK, or the expression of a dominant-negative c-Jun inhibited the TDP-43-induced death in NSC34 motor neuronal cells. These data together suggest that the JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death.