The p35/CDK5 signaling is regulated by p75NTR in neuronal apoptosis after intracerebral hemorrhage
The p35/CDK5 signaling is regulated by p75NTR in neuronal apoptosis after intracerebral hemorrhage
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p35/CDK5信号在脑出血后神经细胞凋亡中受p75NTR调节
DOI：
10.1002/jcp.28244
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Cao, Maohong
中科院分区：
文献类型：
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作者：
Zhou, Tingting;Wang, Hongmei;Cao, Maohong
p75神经营养因子受体（p75NTR）是肿瘤坏死因子受体超家族成员之一，参与脑出血后神经元凋亡。先前已经证明p35的磷酸化是对抗神经元凋亡中促凋亡的p25/CDK5信号传导的关键因素。然后，在大鼠脑出血模型和初级皮质神经元中，我们发现脑出血后p75NTR、p -组蛋白H1 （CDK5的激酶活性）、p25、Fas相关磷酸酶- 1 （FAP - 1）和磷酸化肌细胞增强因子2D （p - MEF2D）的表达增强，而p35 - Thr（138）的表达减弱。共免疫沉淀分析表明，p35/p25与CKD5、p75NTR与p35、p75NTR与FAP‐1等相互作用如下。在PC12细胞中用双链RNA干扰去除p75NTR或FAP‐1后，p25和p‐组蛋白H1的水平降低，而p35‐Thr（138）升高。考虑到p75NTR不具有去磷酸化作用，我们的研究结果表明p75NTR可能通过与FAP‐1的相互作用促进p35‐Thr的去磷酸化（138），p75NTR/p35复合物上调p25/CDK5信号通路，促进脑出血后神经元的凋亡。因此，在本研究中，我们旨在通过调控p75NTR减少脑出血后神经元的凋亡，为潜在的临床治疗提供理论和实验依据。
The p75 neurotrophin receptor (p75NTR), a member of tumor necrosis factor receptor superfamily, involves in neuronal apoptosis after intracerebral hemorrhage (ICH). It has been previously demonstrated that phosphorylation of p35 is a crucial factor for fighting against the proapoptotic p25/CDK5 signaling in neuronal apoptosis. Then, in ICH models of rats and primary cortical neurons, we found that the expressions of p75NTR, p‐histone H1 (the kinase activity of CDK5), p25, Fas‐associated phosphatase‐1 (FAP‐1), and phosphorylated myocyte enhancer factor 2D (p‐MEF2D) were enhanced after ICH, whereas the expression of p35‐Thr(138) was attenuated. Coimmunoprecipitation analysis indicated several interactions as follows: p35/p25 and CKD5, p75NTR and p35, as well as p75NTR and FAP‐1. After p75NTR or FAP‐1 depletion with double‐stranded RNA interference in PC12 cells, the levels of p25 and p‐histone H1 were attenuated, whereas p35‐Thr(138) was elevated. Considering p75NTR has no effect of dephosphorylation, our results suggested that p75NTR might promote the dephosphorylation of p35‐Thr(138) via interaction with FAP‐1, and the p75NTR/p35 complex upregulated p25/CDK5 signaling to facilitate the neuronal apoptosis following ICH. So, in the study, we aimed to provide a theoretical and experimental basis that p75NTR could be regulated to reduce neuronal apoptosis following ICH for potential clinical treatment.