Xu Jing, Li Jia, Sun Ya-Juan, Quan Wei, Liu Li, Zhang Qing-Hui, Qin Yi-Dan, Pei Xiao-Chen, Su Hang, Chen Jia-Jun
Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
Front Neurol. 2023 Mar 9;14:1029370. doi: 10.3389/fneur.2023.1029370. eCollection 2023.
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are collectively known as Lewy body dementia (LBD). Considering the heterogeneous nature of LBD and the different constellations of symptoms with which patients can present, the exact molecular mechanism underlying the differences between these two isoforms is still unknown. Therefore, this study aimed to explore the biomarkers and potential mechanisms that distinguish between PDD and DLB.
The mRNA expression profile dataset of GSE150696 was acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between 12 DLB and 12 PDD were identified from Brodmann area 9 of human postmortem brains using GEO2R. A series of bioinformatics methods were applied to identify the potential signaling pathways involved, and a protein-protein interaction (PPI) network was constructed. Weighted gene co-expression network analysis (WGCNA) was used to further investigate the relationship between gene co-expression and different LBD subtypes. Hub genes that are strongly associated with PDD and DLB were obtained from the intersection of DEGs and selected modules by WGCNA.
A total of 1,864 DEGs between PDD and DLB were filtered by the online analysis tool GEO2R. We found that the most significant GO- and KEGG-enriched terms are involved in the establishment of the vesicle localization and pathways of neurodegeneration-multiple diseases. Glycerolipid metabolism and viral myocarditis were enriched in the PDD group. A B-cell receptor signaling pathway and one carbon pool by folate correlated with DLB in the results obtained from the GSEA. We found several clusters of co-expressed genes which we designated by colors in our WGCNA analysis. Furthermore, we identified seven upregulated genes, namely, SNAP25, GRIN2A, GABRG2, GABRA1, GRIA1, SLC17A6, and SYN1, which are significantly correlated with PDD.
The seven hub genes and the signaling pathways we identified may be involved in the heterogeneous pathogenesis of PDD and DLB.
路易体痴呆（DLB）和帕金森病痴呆（PDD）统称为路易体痴呆（LBD）。鉴于LBD的异质性以及患者可能出现的不同症状组合，这两种亚型之间差异的确切分子机制仍不清楚。因此，本研究旨在探索区分PDD和DLB的生物标志物及潜在机制。
从基因表达综合数据库（GEO）获取GSE150696的mRNA表达谱数据集。使用GEO2R从人类死后大脑的布罗德曼9区中鉴定出12例DLB和12例PDD之间的差异表达基因（DEG）。应用一系列生物信息学方法来确定涉及的潜在信号通路，并构建蛋白质-蛋白质相互作用（PPI）网络。加权基因共表达网络分析（WGCNA）用于进一步研究基因共表达与不同LBD亚型之间的关系。通过WGCNA从DEG与选定模块的交集中获得与PDD和DLB密切相关的枢纽基因。
在线分析工具GEO2R筛选出PDD和DLB之间总共1864个DEG。我们发现最显著富集的GO和KEGG术语涉及囊泡定位的建立以及神经退行性变-多种疾病的途径。甘油脂质代谢和病毒性心肌炎在PDD组中富集。在基因集富集分析（GSEA）获得的结果中，B细胞受体信号通路和叶酸一碳池与DLB相关。我们在WGCNA分析中发现了几个共表达基因簇，并用颜色进行了标记。此外，我们鉴定出7个上调基因，即突触小体相关蛋白25（SNAP25）、谷氨酸受体离子型N-甲基-D-天冬氨酸2A（GRIN2A）、γ-氨基丁酸A型受体γ2亚基（GABRG2）、γ-氨基丁酸A型受体α1亚基（GABRA1）、谷氨酸受体离子型AMPA1（GRIA1）、溶质载体家族17成员6（SLC17A6）和突触蛋白1（SYN1），它们与PDD显著相关。
我们鉴定出的7个枢纽基因和信号通路可能参与了PDD和DLB的异质性发病机制。
