Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, 110001 Liaoning, China.
Cancer Systems Biology Center, The China-Japan Union Hospital, Jilin University, Changchun, 130033 Jilin, China.
Oxid Med Cell Longev. 2022 Feb 3;2022:7619255. doi: 10.1155/2022/7619255. eCollection 2022.
Alzheimer's disease (AD) and Huntington's disease (HD) are destructive worldwide diseases. Efforts have been made to elucidate the process of these two diseases, yet the pathogenesis remains elusive as it involves a combination of multiple factors, including genetic and environmental ones. To explore the potential role of forkhead box O1 (FOXO1) in the development of AD and HD, we identified 1,853 differentially expressed genes (DEGs) from 19,414 background genes in both the AD&HD/control and FOXO1-low/high groups. Four coexpression modules were predicted by the weighted gene coexpression network analysis (WGCNA), among which blue and turquoise modules had the strongest correlation with AD&HD and high expression of FOXO1. Functional enrichment analysis showed that DEGs in these modules were enriched in phagosome, cytokine-cytokine receptor interaction, cellular senescence, FOXO signaling pathway, pathways of neurodegeneration, GABAergic synapse, and AGE-RAGE signaling pathway in diabetic complications. Furthermore, the cross-talking pathways of FOXO1 in AD and HD were jointly determined in a global regulatory network, such as the FOXO signaling pathway, cellular senescence, and AGE-RAGE signaling pathway in diabetic complications. Based on the performance evaluation of the area under the curve of 85.6%, FOXO1 could accurately predict the onset of AD and HD. We then identified the cross-talking pathways of FOXO1 in AD and HD, respectively. More specifically, FOXO1 was involved in the FOXO signaling pathway and cellular senescence in AD; correspondingly, FOXO1 participated in insulin resistance, insulin, and the FOXO signaling pathways in HD. Next, we use GSEA to validate the biological processes in AD&HD and FOXO1 expression. In GSEA analysis, regulation of protein maturation and regulation of protein processing were both enriched in the AD&HD and FOXO1-high groups, suggesting that FOXO1 may have implications in onset and progression of these two diseases through protein synthesis. Consequently, a high expression of FOXO1 is a potential pathogenic factor in both AD and HD involving mechanisms of the FOXO signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and cellular senescence. Our findings provide a comprehensive perspective on the molecular function of FOXO1 in the pathogenesis of AD and HD.
阿尔茨海默病（AD）和亨廷顿病（HD）是全球性的破坏性疾病。人们一直在努力阐明这两种疾病的发病过程，但由于其发病机制涉及多种因素，包括遗传和环境因素，因此仍然难以捉摸。为了探讨叉头框 O1（FOXO1）在 AD 和 HD 发病机制中的潜在作用，我们从 AD&HD/对照组和 FOXO1 低/高组的 19414 个背景基因中鉴定出 1853 个差异表达基因（DEGs）。通过加权基因共表达网络分析（WGCNA）预测了四个共表达模块，其中蓝色和绿松石模块与 AD&HD 和 FOXO1 高表达相关性最强。功能富集分析显示，这些模块中的 DEGs 富集于吞噬体、细胞因子-细胞因子受体相互作用、细胞衰老、FOXO 信号通路、神经退行性变途径、GABA 能突触和糖尿病并发症的 AGE-RAGE 信号通路。此外，在全局调控网络中共同确定了 AD 和 HD 中 FOXO1 的交叉作用途径，如 FOXO 信号通路、细胞衰老和糖尿病并发症中的 AGE-RAGE 信号通路。基于 85.6%的曲线下面积的性能评估，FOXO1 可以准确预测 AD 和 HD 的发病。然后，我们分别确定了 AD 和 HD 中 FOXO1 的交叉作用途径。更具体地说，FOXO1 参与了 AD 中的 FOXO 信号通路和细胞衰老；相应地，FOXO1 参与了 HD 中的胰岛素抵抗、胰岛素和 FOXO 信号通路。接下来，我们使用 GSEA 验证 AD&HD 和 FOXO1 表达中的生物学过程。在 GSEA 分析中，蛋白质成熟的调节和蛋白质加工的调节在 AD&HD 和 FOXO1 高表达组中均富集，表明 FOXO1 可能通过蛋白质合成在这两种疾病的发病和进展中发挥作用。因此，FOXO1 的高表达可能是 AD 和 HD 的潜在致病因素，涉及 FOXO 信号通路、糖尿病并发症中的 AGE-RAGE 信号通路和细胞衰老机制。我们的研究结果为 FOXO1 在 AD 和 HD 发病机制中的分子功能提供了全面的视角。
