Effect of TDP43-CTFs35 on Brain Endothelial Cell Functions in Cerebral Ischemic Injury
Effect of TDP43-CTFs35 on Brain Endothelial Cell Functions in Cerebral Ischemic Injury
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TDP43-CTFs35对脑缺血损伤脑内皮细胞功能的影响
DOI：
10.1007/s12035-022-02869-5
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发表时间：
2022-05
影响因子：
5.1
通讯作者：
Jiukuan Hao
中科院分区：
文献类型：
--
作者：
Xiaotian Xu;Changwen Zhang;Jianxiong Jiang;Mei Xin;Jiukuan Hao
脑内皮的病理变化在缺血性卒中的进展中起重要作用，并且缺血性卒中条件下受损的BBB引起神经元损伤。然而，在正常条件下和缺血性中风条件下的BBB的病理生理机制尚未完全阐明。本研究表明，敲低TAR DNA结合蛋白43（TDP-43）或过表达TDP 43-CTFs 35可抑制脑EC中紧密连接蛋白的表达，以及哺乳动物不育-20样1/2（MST 1/2）和YES相关蛋白（雅普）的磷酸化，并抑制脑EC的体外迁移。脑缺血后24 h和72 h脑ECs胞浆内TDP 43-CTFs 35水平升高，缺血1周后TDP 43-CTFs 35水平消失。MCAO后24 h紧密连接蛋白表达明显下降，72 h和1周时逐渐恢复。雅普磷酸化水平在MCAO后24 h开始显著降低，72 h和1周后升高，并伴有核雅普易位。潜在的机制是TDP 43-CTFs 35介导的通过MST 1/2的去磷酸化抑制Hippo信号传导通路活性，这导致雅普磷酸化的抑制和随后的脑EC迁移和紧密连接蛋白表达的损害。本研究为脑缺血损伤后脑血管EC的调节机制提供了新的见解，这可能会影响BBB的完整性。
Pathological changes in the brain endothelium play an important role in the progression of ischemic stroke and the compromised BBB under ischemic stroke conditions cause neuronal damage. However, the pathophysiological mechanisms of the BBB under normal conditions and under ischemic stroke conditions have not been fully elucidated. The present study demonstrated that knockdown of TAR DNA-binding protein 43 (TDP-43) or overexpression of TDP43-CTFs35 inhibited tight junction protein expression, and mammalian sterile-20-like 1/2 (MST1/2) and YES-associated protein (YAP) phosphorylation in brain ECs and suppressed brain EC migration in vitro. The cytoplasmic TDP43-CTFs35 level was increased in brain ECs 24 h and 72 h after MCAO, but it disappeared 1 week after cerebral ischemia. The expression of tight junction proteins was also significantly deceased 24 h after MCAO and then gradually recovered at 72 h and 1 week after MCAO. The level of YAP phosphorylation was first significantly decreased 24 h after MCAO and then increased 72 h and 1 week after MCAO, accompanied by nuclear YAP translocation. The underlying mechanism is TDP43-CTFs35-mediated inhibition of Hippo signaling pathway activity through the dephosphorylation of MST1/2, which leads to the inhibition of YAP phosphorylation and the subsequent impairment of brain EC migration and tight junction protein expression. This study provides new insights into the mechanisms of brain vascular EC regulation, which may impact on BBB integrity after cerebral ischemic injury.
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影响因子：
7.2
作者：
Selkoe, Dennis J.
通讯作者：
Selkoe, Dennis J.
影响因子：
168.9
作者：
Ballard, Clive;Gauthier, Serge;Jones, Emma
通讯作者：
Jones, Emma
影响因子：
8
作者：
Oka, T.;Schmitt, A. P.;Sudol, M.
通讯作者：
Sudol, M.
DOI：
10.3109/21678421.2012.734520
发表时间：
2013-05-01
影响因子：
2.8
作者：
Narayanan, Ramesh K.;Mangelsdorf, Marie;Wallace, Robyn H.
通讯作者：
Wallace, Robyn H.
影响因子：
3.7
作者：
Armanini, D;Vecchio, F;Karbowiak, I
通讯作者：
Karbowiak, I