PRMT6影响SIRT3可变剪切调控CypD乙酰化水平介导脓毒症脑病时线粒体损伤的机制研究

脓毒症脑病(SAE)是脓毒症的严重并发症，影响患者预后，目前尚无有效防治手段。我们前期研究证实海马神经元凋亡参与SAE的病理过程，机制不清。预实验发现SAE小鼠海马神经元PRMT6上调，PRMT6敲除小鼠SAE时细胞凋亡减少、认知功能改善；进一步研究证实PRMT6通过CypD-mPTP调控神经元线粒体损伤；筛查发现PRMT6影响SIRT3可变剪切，调控CypD乙酰化水平；数据库预测提示SIRT3基因外显子中有可变剪切的识别序列和结合位点。由此推测：SAE时海马神经元PRMT6表达上调，影响SIRT3可变剪切，上调CypD乙酰化水平，促进mPTP过度开放，导致线粒体损伤并介导神经元凋亡。本项目拟系统探讨PRMT6在SAE时线粒体损伤介导海马神经元凋亡中的作用，并探索PRMT6→SIRT3→CypD轴在神经元线粒体损伤中的作用及分子机制。研究结果将为临床上防治SAE提供潜在靶点。

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, affecting the prognosis of patients. Currently, there is no effective prevention and treatment. Our previous study confirmed that hippocampal neuron apoptosis involved in the pathology of SAE, but the mechanism is unclear. Firstly, we found that PRMT6 was up-regulated in hippocampus of SAE mice. And PRMT6-/- mice showed reduced apoptosis and improved cognition. Secondly, we confirmed that PRMT6 mediated mitochondrial damage by regulating CypD-mPTP. Furtherly, screening experiment revealed that modulation of SIRT3 alternative splicing by PRMT6 regulated CypD acetylation status. Database prediction suggests that there are alternative splicing recognition sequences and binding sites in SIRT3 gene exon. Therefore, we speculate that upregulation of PRMT6 in hippocampus modulated SIRT3 pre-mRNA splicing and thus increased CypD acetylation which promoted the opening of mPTP, leading to mitochondrial damage and neuron apoptosis in SAE. In this project, we will systematically explore the role of PRMT6 in mitochondrial damage and neuron apoptosis in SAE. We will also study the underlying mechanism of “PRMT6→SIRT3→CypD” in mitochondrial damage in SAE. The results may provide a reference for clinical prevention and treatment of SAE.