LncRNA MAFIP在帕金森病神经免疫炎症中的作用及分子机制

Parkinson's disease (PD) is a disabling degenerative disease of central nervous system with a high incidence. The underlying mechanism in the pathogenesis of PD remains unclear. Long noncoding RNA (LncRNA) is involved in the regulation of gene expression at epigenetics, transcriptional and post-transcriptional levels. Our preliminary study found that the expression of LncRNA MAFIP was significantly down-regulated in the leukocytes from peripheral blood of PD patients compared to healthy controls. Previous studies have shown that LncRNA MAFIP could inhibit the activation of NF-κB signaling pathway, and the abnormal activation of NF-κB could up-regulate the expression of NLRP3 inflammasome，which promotes the occurrence of neuroinflammation in PD. Therefore, we hypothesize that LncRNA MAFIP downregulation attenuates NF-κB signaling pathway in microglia, resulting in activation of NLRP3 inflammasome and aggravating neuroinflammatory response, which play a vital role in the pathogenesis of PD. This study aims to reveal the role of NF-κB-NLRP3 signaling pathway in the pathogenesis of PD from the perspective of LncRNA, which will provide new targets for the treatment of PD.

帕金森病（Parkinson's disease, PD）是高发病率的致残性中枢神经系统变性疾病，其发病机制尚未阐明。长链非编码RNA(LncRNA)在表观修饰水平、转录及转录后水平参与基因表达的调控。我们在前期工作中发现LncRNA MAFIP在PD患者的外周血白细胞中的表达显著下调，有报道LncRNA MAFIP可以抑制NF-κB信号通路的激活，而NF-κB的异常激活可以上调NLRP3炎症小体的表达，促进PD免疫炎症的发生。因此，我们推测小胶质细胞中LncRNA MAFIP下调引起对NF-κB信号通路抑制作用减弱，导致NLRP3炎症小体通路激活，加重神经免疫炎症反应而参与PD发病。本课题旨在从LncRNA的角度揭示NF-κB—NLRP3信号通路在PD免疫炎症发病机制中的作用及分子机制，将为PD的治疗提供新的靶点。

帕金森病（Parkinson’s disease; PD）是第二常见的神经退行性疾病，主要病理表现为路易小体沉积和多巴胺神经元进行性丢失。近年来，研究者发现免疫系统异常激活和神经炎症的发生与PD的发病密切相关。长链非编码RNA(LncRNA)可通过调控基因表达进而影响免疫细胞活化和神经炎症的发生。我们通过分析PD患者和健康对照的循环白细胞中的lncRNA和mRNA表达，四个lncRNA（AC131056.3-001、HOTAIRM1、lnc-MOK-6：1 和 RF01976.1-201）在PD患者的外周白细胞中上调。通过KEGG分析和基因富集对表达改变的基因功能进行分析，结果显示：在与PD发病机制相关的生物学通路，免疫应答，炎症应答，MAPK和Jak-STAT通路可能发挥了重要作用。此外，LPS和IFN-γ刺激单核细胞系（THP-1）的条件培养基可显着增加人神经母细胞瘤细胞系SH-SY5Y细胞中四种lncRNA的表达，这表明炎性环境可能通过调控lncRNA的表达进而影响神经炎症的发生。通过体外实验，我们证实了AC131056.3-001或HOTAIRM1的过表达可增加6-OHDA诱导的SH-SY5Y细胞凋亡。综上，我们发现PD患者和健康对照者之间循环白细胞中存在不同的lncRNA和mRNA表达谱，且表达改变的 lncRNA和mRNA之间存在很强的相关性。我们首次证明了AC131056.3-001或HOTAIRM1影响了细胞活力并促进了SH-SY5Y细胞的凋亡。该结论可能为PD的诊断提供潜在的生物标志物，为PD的免疫炎症机制提供新的方向。目前已发表和收稿文章3篇，2篇文章已发表于SCI期刊。培养博士生1名，硕士生2名。