Sun Rui-Xue, Guo Yan
Department of Internal Medicine, Nanjing Luhe District Zhu Town Community Health Service Center, Nanjing, Jiangsu, China.
Eur J Med Res. 2025 Apr 15;30(1):278. doi: 10.1186/s40001-025-02554-y.
Parkinson's disease (PD), a progressive neurodegenerative disease, still lacks disease-modifying treatment strategies. The formation of Lewy body is the typical pathological feature of PD. Pathological progression can be defined by Braak stages. However, the molecular mechanism for this ascending course of α-synuclein pathology remains unclear.
In this study, weighted gene co-expression network analysis (WGCNA) was used to screen Braak stage-related gene signatures, followed by the functional enrichment analysis, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA). The hub genes were screened through CytoHubba and Least Absolute Shrinkage and Selection Operator (LASSO) analysis. The immune cell proportion was predicted by the ImmuCellAI. Furthermore, transcription factors (TFs) and miRNAs targeting the hub genes network were constructed. After verifying hub gene expression level through independent data sets. The validated hub gene was further analyzed to elucidate the potential molecular mechanism.
Total of 388 genes associated with Braak stages were screened out through WGCNA analysis. The KEGG analysis showed that these genes were involved in endocytosis, HIF-1 signaling pathway, synaptic vesicle cycle, dopaminergic synapse, oxytocin signaling pathway, etc. Immune infiltration analysis showed that CD4 + T cells, including nTreg, Th2, and Th17, were obviously different between different Braak stages in PD. Furthermore, eights Braak stages-related hub genes were identified, including CAMK2B, CPLX2, GAPDH, GRIN1, KCNA1, MAPK3, MAPT, and STXBP1 through the cytoHubba plugin and LASSO analysis. After verifying the expression level in three independent data sets, CPLX2 was finally identified as the most reliable Braak stages-associated hub genes in PD.
This study revealed the Braak stage-related gene signatures in PD and identified CPLX2 as a novel Braak stages-related hub gene in PD, which provided a novel target for future therapeutic interventions and disease markers. The specific molecular mechanism of CPLX2 in PD remained to be further clarified.
帕金森病（PD）是一种进行性神经退行性疾病，仍然缺乏疾病修饰治疗策略。路易小体的形成是PD的典型病理特征。病理进展可通过Braak分期来定义。然而，α-突触核蛋白病理这种上升过程的分子机制仍不清楚。
在本研究中，使用加权基因共表达网络分析（WGCNA）来筛选与Braak分期相关的基因特征，随后进行功能富集分析，包括基因本体（GO）、京都基因与基因组百科全书（KEGG）和基因集富集分析（GSEA）。通过CytoHubba和最小绝对收缩和选择算子（LASSO）分析筛选枢纽基因。通过ImmuCellAI预测免疫细胞比例。此外，构建了靶向枢纽基因网络的转录因子（TFs）和微小RNA（miRNAs）。通过独立数据集验证枢纽基因表达水平后，对验证后的枢纽基因进行进一步分析以阐明潜在的分子机制。
通过WGCNA分析筛选出总共388个与Braak分期相关的基因。KEGG分析表明这些基因参与内吞作用、缺氧诱导因子-1信号通路、突触小泡循环、多巴胺能突触、催产素信号通路等。免疫浸润分析表明，包括nTreg、Th2和Th17在内的CD4 + T细胞在PD的不同Braak分期之间存在明显差异。此外，通过CytoHubba插件和LASSO分析确定了8个与Braak分期相关的枢纽基因，包括钙/钙调蛋白依赖性蛋白激酶2B（CAMK2B）、复杂性2（CPLX2）、甘油醛-3-磷酸脱氢酶（GAPDH）、谷氨酸离子型受体NMDA 1型亚基（GRIN1）、钾电压门控通道亚家族A成员1（KCNA1）、丝裂原活化蛋白激酶3（MAPK3）、微管相关蛋白Tau（MAPT）和 syntaxin结合蛋白1（STXBP1）。在三个独立数据集中验证表达水平后，CPLX2最终被确定为PD中最可靠的与Braak分期相关的枢纽基因。
本研究揭示了PD中与Braak分期相关的基因特征，并确定CPLX2为PD中一个新的与Braak分期相关的枢纽基因，这为未来的治疗干预和疾病标志物提供了一个新靶点。CPLX2在PD中的具体分子机制仍有待进一步阐明。
