Abstract：
Epilepsy is a neurological disorder characterized by recurring seizures. It is necessary to further understand the mechanisms of epilepsy in order to develop novel strategies for its prevention and treatment. Abnormal endoplasmic reticulum stress (ERS) activation is related to the pathogenesis of epilepsy. Nuclear protein 1, transcriptional regulator (NUPR1) is involved in ERS and it might play a role in epilepsy progression. In the present study, we generated an epileptic mouse model using pilocarpine induction. After 72 h of pilocarpine treatment, the expression of NUPR1 was increased in epileptic mice. Furthermore, NUPR1 knockdown reduced the number of spontaneous recurrent seizures and alleviated hippocampal damage in these mice. Interestingly, NUPR1 knockdown also reduced the protein expression levels of LC3, PINK1, and Parkin in the mitochondria, and decreased the PINK1 expression in hippocampus. Additionally, the expression of ERS-related proteins-cleaved caspase-12, ATF4, and CHOP-decreased in epileptic mice following NUPR1 knockdown. In vitro experiments showed that the absence of NUPR1 reduced the expression of ATF4, CHOP, and cleaved caspase-12 in hippocampal neurons and inhibited the neuron apoptosis. In all, our study suggested that NUPR1 maybe a potential molecular target for epilepsy therapy.
摘要：
癫痫是一种以反复发作为特征的神经系统疾病。有必要进一步了解癫痫的机制，以开发新的预防和治疗策略。异常内质网应激(ERS)激活与癫痫的发病机制有关。核蛋白1，转录调节因子（NUPR1）参与ERS，它可能在癫痫的进展中起作用。在本研究中,我们使用毛果芸香碱诱导产生了癫痫小鼠模型。毛果芸香碱治疗72小时后，NUPR1在癫痫小鼠中的表达增加。此外，NUPR1敲除减少了这些小鼠的自发性复发性癫痫发作的数量并减轻了海马损伤。有趣的是,NUPR1敲低也降低了线粒体中LC3、PINK1和Parkin的蛋白表达水平,海马PINK1表达降低。此外,在NUPR1敲低后癫痫小鼠中,ERS相关蛋白裂解的caspase-12、ATF4和CHOP的表达降低。体外实验表明，NUPR1的缺失降低了ATF4、CHOP的表达，并裂解海马神经元caspase-12，抑制神经元凋亡。总之,我们的研究提示NUPR1可能是癫痫治疗的潜在分子靶点.
