MDH2 is an RNA binding protein involved in downregulation of sodium channel Scn1a expression under seizure condition
MDH2 is an RNA binding protein involved in downregulation of sodium channel Scn1a expression under seizure condition
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MDH2 是一种 RNA 结合蛋白，参与癫痫发作时钠通道 Scn1a 表达的下调
DOI：
10.1016/j.bbadis.2017.04.018
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发表时间：
2017-06-01
影响因子：
6.2
通讯作者：
Long, Yue-Sheng
中科院分区：
文献类型：
--
作者：
Chen, Yong-Hong;Liu, Shu-Jing;Long, Yue-Sheng
电压门控钠通道α亚基I（Na（v）1.1，由SCN 1A基因编码）在脑兴奋性中起着重要作用。SCN 1A表达下调与癫痫有关，癫痫是一种以反复发作为特征的常见神经系统疾病。在这里，我们揭示了一个新的作用，苹果酸脱氢酶2（MDH 2）在转录后调控的SCN 1A表达癫痫发作条件下。我们鉴定MDH 2是一种RNA结合蛋白，其可以结合SCN 1A的3'UTR中的四个保守区域中的两个。我们进一步表明，在HEK-293细胞中MDH 2的敲低或MDH 2活性的失活通过SCN 1A的3' UTR增加报告基因的表达，MDH 2过表达通过影响mRNA稳定性降低基因表达。在癫痫发作小鼠海马中，MDH 2表达上调导致Nav1.1在转录后水平的表达降低。此外，H202可促进MDH 2与Scn 1a基因结合位点的结合，而P-巯基乙醇则可降低MDH 2与Scn 1a基因结合位点的结合能力，表明癫痫诱导的氧化对MDH 2介导的Scn 1a表达下调具有重要作用。总之，这些数据表明，MDH 2，作为一种RNA结合蛋白，参与转录后下调SCN 1A表达癫痫发作条件下。
Voltage-gated sodium channel alpha-subunit type I (Na(v)1.1, encoded by SCN1A gene) plays a critical role in the excitability of brain. Downregulation of SCN1A expression is associated with epilepsy, a common neurological disorder characterized by recurrent seizures. Here we reveal a novel role of malate dehydrogenase 2 (MDH2) in the posttranscriptional regulation of SCN1A expression under seizure condition. We identified that MDH2 was an RNA binding protein that could bind two of the four conserved regions in the 3' UTRs of SCN1A. We further showed that knockdown of MDH2 or inactivation of MDH2 activity in HEK-293 cells increased the reporter gene expression through the 3' UTR of SCN1A, and MDH2 overexpression decreased gene expression by affecting mRNA stability. In the hippocampus of seizure mice, the upregulation of MDH2 expression contributed to the decrease of the Nav1.1 levels at posttranscriptional level. In addition, we showed that the H202 levels increased in the hippocampus of the seizure mice, and H202 could promote the binding of MDH2 to the binding sites of Scn1a gene, whereas P-mercaptoethanol decreased the binding capability, indicating an important effect of the seizure-induced oxidation on the MDH2-mediated downregulation of Scn1a expression. Taken together, these data suggest that MDH2, functioning as an RNA-binding protein, is involved in the posttranscriptional downregulation of SCN1A expression under seizure condition.