帕金森病中与氧化应激相关的中枢基因的鉴定与验证

IF 4.6 2区医学 Q1 NEUROSCIENCES

Molecular Neurobiology Pub Date : 2024-11-18 DOI:10.1007/s12035-024-04622-6

Lina Zhu, Deng Chen, Xiangxiu Wang, Chengqi He

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引用次数: 0

摘要

越来越多的证据表明，氧化应激在帕金森病（PD）的发病机制中起着至关重要的作用。本研究旨在识别氧化应激相关的枢纽基因，通过构建诊断模型对其进行验证，探索它们与 miRNA 和转录因子（TFs）的相互作用，并预测潜在的药物靶点。通过分析从 GEO 数据库（包括 GSE7621、GSE20141、GSE49036 和 GSE20163）中选取的数据集组合，确定了帕金森病患者黑质中的差异表达基因（DEGs）。通过加权基因共表达网络分析（WGCNA）确定的DEGs、氧化应激相关基因（OSGs）和关键模块中具有最高相关值的基因之间的重叠度，筛选出与氧化应激相关的候选基因。基因本体（GO）和京都基因组百科全书（KEGG）数据库用于对这些候选基因进行功能富集分析。通过蛋白-蛋白相互作用（PPI）分析确定了中枢基因，并构建了接收者操作特征曲线（ROC）来评估每个中枢基因的诊断价值。然后，通过最小绝对收缩和选择算子（LASSO）回归，利用上述确定的中心基因构建了诊断模型，并在外部验证数据集（GSE20292 和 GSE20164）中进一步验证了该模型。基因-miRNA 和基因-TF 调控网络是通过 miRNet 数据库预测的，而候选药物则是通过药物-基因相互作用数据库预测的。对通过 WGCNA 确定的 7975 个 DEGs、434 个 OSGs 和 3582 个基因进行交叉分析后，确定了 76 个候选基因。通过PPI和ROC曲线分析，共确定了9个中心基因（JUN、KEAP1、SRC、GPX5、MMP9、TXN、MAPK3、GPX2和IL1A）。根据已确定的枢纽基因，构建了一个能够可靠预测帕金森病的诊断模型（AUC = 0.925）。对这9个基因的进一步分析发现了64个靶向miRNA、35个调控网络中的TFs和86种潜在治疗药物。结果发现了九个与帕金森病发病机制中氧化应激有关的中枢基因。这些基因具有很强的诊断能力，可作为治疗靶点。这些发现可能有助于开发有前景的候选生物标记物和潜在的帕金森病疾病调节疗法。

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Identification and Validation of Oxidative Stress-Related Hub Genes in Parkinson's Disease.

Accumulating evidence suggests that oxidative stress plays a crucial role in the pathogenesis of Parkinson's disease (PD). The aims of this study were to identify oxidative stress-related hub genes, validate them through the construction of a diagnostic model, explore their interactions with miRNAs and transcription factors (TFs) and predict potential drug targets. Differentially expressed genes (DEGs) in the substantia nigra of PD patients were identified by analyzing a combination of datasets selected from the GEO database, including GSE7621, GSE20141, GSE49036, and GSE20163. The candidate genes associated with oxidative stress were screened by determining the overlap among the DEGs, oxidative stress-related genes (OSGs) and genes in key modules with the highest cor values identified via weighted gene coexpression network analysis (WGCNA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to perform functional enrichment analysis of these candidate genes. The hub genes were identified via protein-protein interaction (PPI) analysis, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic value of each hub gene. Then, a diagnostic model was constructed via least absolute shrinkage and selection operator (LASSO) regression with the hub genes identified above, and the model was further validated in external validation datasets (GSE20292 and GSE20164). Gene-miRNA and gene-TF regulatory networks were predicted via the miRNet database, whereas candidate drugs were predicted via the Drug-Gene Interaction database. After analysis of the intersection of the 7975 DEGs, 434 OSGs, and 3582 genes identified through WGCNA, 76 candidate genes were identified. A total of 9 hub genes (JUN, KEAP1, SRC, GPX5, MMP9, TXN, MAPK3, GPX2, and IL1A) were identified via PPI and ROC curve analyses. A diagnostic model with the ability to reliably predict PD on the basis of the identified hub genes (AUC = 0.925) was constructed. Further analysis of these 9 genes revealed 64 targeted miRNAs, 35 TFs in regulatory networks and 86 potential therapeutic agents. Nine hub genes related to oxidative stress in the pathogenesis of PD were identified. These genes show strong diagnostic performance and could serve as therapeutic targets. These findings might facilitate the development of promising candidate biomarkers and potential disease-modifying therapies for PD.

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来源期刊

Molecular Neurobiology 医学-神经科学

CiteScore

9.00

自引率

2.00%

发文量

480

审稿时长

1 months

期刊介绍： Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.