阿尔茨海默病铁死亡相关miRNA-mRNA关系对的挖掘

Exploration of miRNA-mRNA Relationship Pairs Related to Iron Death in Alzheimer’s Disease

摘要: 目的：阿尔茨海默病(Alzheimer’s disease, AD)在老年及老年前期呈多发形式、以行为损害与进行性认知功能障碍为特征，是一种中枢神经系统退行性病变。大量研究表明，AD的发病与基因调控有关，研究miRNA靶向mRNA的调控机制对疾病研究以及治疗具有一定的前瞻性。铁死亡是一种以细胞内铁沉积为特征的细胞死亡形式，在形态、生化、遗传上区别于细胞凋亡、自噬及程序性坏死，在神经退行性病变中起着重要作用。本研究通过探究与阿尔茨海默病相关的miRNA和mRNA调控关系对与铁死亡之间的联系，为完善AD的发病机制与治疗方法提供参考。方法：我们在NCBI数据库中以Alzheimer’s disease、Homo、mRNA/miRNA为关键词筛选表达谱，选择在脑部差异表达的mRNA与miRNA。将每个表达谱中筛选出的差异表达miRNA与mRNA取交集。通过铁死亡数据库FerrDb，分别下载促进铁死亡基因、抑制铁死亡基因的数据集，将差异表达mRNA与其分别取交集获得目标mRNA；根据表达量排序，得到在阿尔茨海默病中表达上调的miRNA与表达下调的miRNA。对目标miRNA通过miRWalk3.0数据库进行预测，将靶向mRNA与目标mRNA取交集，并用cytoscape3.9.1构建miRNA-mRNA网络关系图，最终得出与阿尔茨海默病铁死亡有关的miRNA-mRNA调控关系对，为完善AD的发病机制与治疗方法提供参考。结果：hsa-miR-3065在AD中下调，其靶向调控基因DRG1，PIK3CA，TF，SLC38A1，ATG16L1，SNX4，SOCS1，MAPK8，PRKAA2，HIF1A，IFNG，HMGB1，TNFAIP3，TLR4，ATF3，SNX5，DDR2在AD中上调，对铁死亡起促进作用；has-miR-4443在AD中上调，其靶向调控基因PRR5，AKR1C1，SRC，TP63，CISD2，BRD4，SESN2，AIFM2，LAMP2，FXN，SUV39H1，ATF2，NEDD4L，TF，BRD3，NCOA3，TFAM，NUPR1，PARP12，CREB5，ASAH2，CHMP1A，CAMKK2，SOX2，MEF2C，MARCHF5，TRIB2，PDK4，PTPN18，ABCC5，FURIN在AD中下调，对铁死亡起抑制作用。结论：本实验所挖掘的miRNA-mRNA关系对与铁死亡及阿尔茨海默病有关，同向促进或抑制二者的发展。

Abstract: Objective: Alzheimer’s disease (AD) is a degenerative central nervous system disorder characterized by behavioral impairment and progressive cognitive impairment, which is more common in the elderly and pre elderly. Numerous studies have shown that the pathogenesis of Alzheimer’s disease is related to gene regulation, and studying the regulatory mechanism of miRNA targeting mRNA has certain prospects for disease research and treatment. Iron death is a form of cell death characterized by intracellular iron deposition, which differs from apoptosis, autophagy, and programmed necrosis in morphology, biochemistry, and genetics. It plays an important role in neurodegenerative diseases. This study explores the relationship between miRNA and mRNA regulation related to Alzheimer’s disease and iron death to provide reference for improving the pathogenesis and treatment methods of AD. Method: We screened the expression profile using Alzheimer’s disease, Homo, mRNA/miRNA as keywords in the NCBI database, and selected mRNA and miRNA differentially expressed in the brain. The differentially expressed miRNAs and mRNAs screened in each expression profile were taken as intersections. Through the iron death database FerrDb, the datasets of iron death-promoting genes and iron death-suppressing genes were downloaded separately, and the differentially expressed mRNAs were intersected with them to obtain the target mRNAs. According to the expression level ranking, upregulated miRNAs and downregulated miRNAs were obtained in Alzheimer’s disease. Using the miRWalk3.0 database to predict target miRNAs, taking the intersection of target mRNA and the above mentioned target mRNA, and constructing a miRNA-mRNA network using Cytoscape 3.9.1, ultimately obtaining the regulatory relationship of miRNA-mRNA related to iron death in Alzheimer’s disease, providing reference for improving the pathogenesis and treatment methods of AD. Result: The miRNA hsa-miR-3065 is downregulated in AD, and it’s targeted regulatory genes NDRG1, PIK3CA, TF, SLC38A1, ATG16L1, SNX4, SOCS1, MAPK8, PRKAA2, HIF1A, IFNG, HMGB1, TNFAIP3, TLR4, ATF3, SNX5, DDR2 are upregulated in Alzheimer’s disease which promote iron death. The mi-RNA hsa-miR-4443 is upregulated in Alzheimer’s disease, and it’s targeted regulatory genes PRR5, AKR1C1, SRC, TP63, CISD2, BRD4, SESN2, AIFM2, LAMP2, FXN, SUV39H1, ATF2, NEDD4L, TF, BRD3, NCOA3, TFAM, NUPR1, PARP12, CREB5, ASAH2, CHMP1A, CAMKK2, SOX2, MEF2C, MARCHF5, TRIB2, PDK4, PTPN18, ABCC5, FURIN are underregulated in AD witch suppress iron death. Conclusion: This study explored miRNA-mRNA related to iron death in Alzheimer’s disease that promotes or suppresses both of two in the same direction.