Phosphoglycerate kinase (PGK) 1 succinylation modulates epileptic seizures and the blood-brain barrier.
Phosphoglycerate kinase (PGK) 1 succinylation modulates epileptic seizures and the blood-brain barrier.
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DOI：
10.1538/expanim.23-0019
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发表时间：
2023-11-09
影响因子：
2.4
通讯作者：
Zhang, Haiqing
中科院分区：
文献类型：
--
作者：
Luo, Yuemei;Yang, Juan;Zhang, Lijia;Tai, Zhenzhen;Huang, Hao;Xu, Zucai;Zhang, Haiqing
关键词：
癫痫是神经系统中最常见的慢性疾病，主要特征是反复发作、周期性发作和不可预测的发作。翻译后修饰（Post-translational modification，PTM）是重要的蛋白质功能调节因子，参与调节多种生理和病理过程。它对细胞活性、稳定性、蛋白质折叠和定位具有重要意义。磷酸甘油酸激酶（PGK）1是糖酵解途径中重要的三磷酸腺苷（ATP）生成酶。PGK 1催化磷酰基从1，3-二磷酸甘油酸（1，3-BPG）可逆转移到ADP，产生3-磷酸甘油酸（3-PG）和ATP。除了细胞代谢调节外，PGK 1还参与多种生物学活动，包括血管生成、自噬和DNA修复。然而，PGK 1琥珀酰化在癫痫中的确切作用尚未得到彻底研究。通过免疫沉淀法分析PGK 1琥珀酰化的表达。Western印迹法用于评估PGK 1、血管抑素和血管内皮生长因子（VEGF）在锂-匹罗卡品诱导的急性癫痫大鼠模型中的表达。在锂-匹罗卡品诱导的急性癫痫大鼠模型中进行行为学实验。采用ELISA法检测血清脑标志物S100β水平，判断血脑屏障的完整性。与正常大鼠相比，在锂-匹罗卡品诱导的急性癫痫大鼠模型中，海马中PGK 1琥珀酰化的表达降低。有趣的是，慢病毒的赖氨酸15（K15）和精氨酸（R）变体增加了锂-匹鲁卡品诱导的急性癫痫大鼠模型的易感性，而谷氨酸（E）变体K15具有相反的作用。此外，PGK 1在K15的琥珀酰化影响PGK 1琥珀酰化的表达，但不影响PGK 1总蛋白的表达。此外，研究发现PGK 1在K15处的琥珀酰化可能影响海马中血管抑素和VEGF的水平，这也影响血清中S100β的水平。结论：PGK 1 K15位点突变可能通过改变PGK 1琥珀酰化的表达，进而通过血管抑素/ VEGF通路影响血脑屏障的完整性，从而改变癫痫的活动性，这可能是治疗癫痫的新策略之一。
Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications (PTMs) are important protein functional regulators that regulate various physiological and pathological processes. It is significant for cell activity, stability, protein folding, and localization. Phosphoglycerate kinase (PGK) 1 has traditionally been studied as an important adenosine triphosphate (ATP)-generating enzyme of the glycolytic pathway. PGK1 catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. In addition to cell metabolism regulation, PGK1 is involved in multiple biological activities, including angiogenesis, autophagy, and DNA repair. However, the exact role of PGK1 succinylation in epilepsy has not been thoroughly investigated. The expression of PGK1 succinylation was analyzed by Immunoprecipitation. Western blots were used to assess the expression of PGK1, angiostatin, and vascular endothelial growth factor (VEGF) in a rat model of lithium-pilocarpine-induced acute epilepsy. Behavioral experiments were performed in a rat model of lithium-pilocarpine-induced acute epilepsy. ELISA method was used to measure the level of S100β in serum brain biomarkers’ integrity of the blood-brain barrier. The expression of the succinylation of PGK1 was decreased in a rat model of lithium-pilocarpine-induced acute epilepsy compared with the normal rats in the hippocampus. Interestingly, the lysine 15 (K15), and the arginine (R) variants of lentivirus increased the susceptibility in a rat model of lithium-pilocarpine-induced acute epilepsy, and the K15 the glutamate (E) variants, had the opposite effect. In addition, the succinylation of PGK1 at K15 affected the expression of PGK1 succinylation but not the expression of PGK1total protein. Furthermore, the study found that the succinylation of PGK1 at K15 may affect the level of angiostatin and VEGF in the hippocampus, which also affects the level of S100β in serum. In conclusion, the mutation of the K15 site of PGK1 may alter the expression of the succinylation of PGK1 and then affect the integrity of the blood-brain barrier through the angiostatin / VEGF pathway altering the activity of epilepsy, which may be one of the new mechanisms of treatment strategies.
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