Liu Tingting, Li Jingwen, Zhang Junshi, Wei Jianshe
Institute for Brain Sciences Research, School of Life Sciences, Henan University, Institute of Neurourology and Urodynamics, Huaihe Hospital of Henan University, Kaifeng, the People's Republic of China.
PLoS One. 2025 Jul 17;20(7):e0327550. doi: 10.1371/journal.pone.0327550. eCollection 2025.
Parkinson's disease (PD), a neurodegenerative condition characterized by the loss of dopamine neurons and motor deficits, has recently been associated with cuproptosis, a process potentially leading to mitochondrial dysfunction. This study utilized six PD datasets from the GEO database, designating one for internal training and the remaining five for external validation. Various analytical methods, such as Gene Set Enrichment Analysis (GSEA), immune infiltration studies, and differential expression analysis, were employed to pinpoint differentially expressed genes (DEGs). The research also applied Weighted Gene Co-expression Network Analysis (WGCNA) to identify module genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. By intersecting DEGs with cuproptosis-related genes (CRGs), differentially expressed cuproptosis-related genes (DECRGs) were identified and assessed using Receiver Operating Characteristic (ROC) curves. Further analysis led to the discovery of differentially expressed cuproptosis-mitochondrial dysfunction-related genes (DEC-MDRGs), which were validated and subjected to additional scrutiny. The study concluded with predictions of potential therapeutic drugs. The findings revealed 6685 DEGs and 31 distinct modules, with gene functions predominantly enriched in immune-related pathways. Twelve DECRGs, recognized as high-diagnostic-potential hub genes (AUC > 0.9), were identified for early PD diagnosis. Additionally, eight DEC-MDRGs were found to be expressed across various neural cells. The miRNA network highlighted the significance of miR-4632 and miR-637. In a MPTP-induced mouse model of PD, differential gene expression was confirmed through gene and protein analysis. Transmission electron microscopy (TEM) uncovered mitochondrial alterations in SH-SY5Y cells. Potential PD treatments, including NADH, Radicipol, and Glycine, were also identified. In summary, advancements in PD prevention, diagnosis, and treatment can be achieved by modulating copper metabolism and mitochondrial function, thereby enhancing the quality of life for patients.
帕金森病（PD）是一种以多巴胺神经元丧失和运动功能障碍为特征的神经退行性疾病，最近被发现与铜死亡有关，这一过程可能导致线粒体功能障碍。本研究使用了来自基因表达综合数据库（GEO）的六个帕金森病数据集，指定其中一个用于内部训练，其余五个用于外部验证。采用了多种分析方法，如基因集富集分析（GSEA）、免疫浸润研究和差异表达分析，以确定差异表达基因（DEG）。该研究还应用加权基因共表达网络分析（WGCNA）来识别模块基因，随后进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析。通过将DEG与铜死亡相关基因（CRG）进行交叉分析，鉴定出差异表达的铜死亡相关基因（DECRG），并使用受试者工作特征（ROC）曲线进行评估。进一步分析发现了差异表达的铜死亡-线粒体功能障碍相关基因（DEC-MDRG），对其进行了验证并进行了额外的审查。该研究最后对潜在的治疗药物进行了预测。研究结果揭示了6685个DEG和31个不同的模块，基因功能主要富集在免疫相关途径中。确定了12个DECRG作为具有高诊断潜力的枢纽基因（AUC>0.9），用于帕金森病的早期诊断。此外，发现8个DEC-MDRG在各种神经细胞中表达。miRNA网络突出了miR-4632和miR-637的重要性。在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病小鼠模型中，通过基因和蛋白质分析证实了基因表达的差异。透射电子显微镜（TEM）发现了SH-SY5Y细胞中的线粒体改变。还确定了包括烟酰胺腺嘌呤二核苷酸（NADH）、雷迪波尔和甘氨酸在内的潜在帕金森病治疗方法。总之，通过调节铜代谢和线粒体功能，可以实现帕金森病预防、诊断和治疗的进展，从而提高患者的生活质量。
