Integrative transcriptomic and proteomic analysis reveals that SERPING1 inhibits neuronal proliferation via the CaMKII-CREB-BDNF pathway in schizophrenia.

IF 3.9 4区医学 Q1 PSYCHIATRY

World Journal of Psychiatry Pub Date : 2025-02-19 DOI:10.5498/wjp.v15.i2.100214

Feng Li, Xing Ren, Jia-Xiu Liu, Tian-Dao Wang, Bi Wang, Xiao-Bin Wei

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Abstract

Background: Schizophrenia (SZ), a chronic and widespread brain disorder, presents with complex etiology and pathogenesis that remain inadequately understood. Despite the absence of a universally recognized endophenotype, peripheral blood mononuclear cells (PBMCs) serve as a robust model for investigating intracellular alterations linked to SZ.

Aim: To preliminarily investigate potential pathogenic mechanisms and identify novel biomarkers for SZ.

Methods: PBMCs from SZ patients were subjected to integrative transcriptomic and proteomic analyses to uncover differentially expressed genes (DEGs) and differentially expressed proteins while mapping putative disease-associated signaling pathways. Key findings were validated using western blot (WB) and real-time fluorescence quantitative PCR (RT-qPCR). RNAi-lentivirus was employed to transfect rat hippocampal CA1 neurons in vitro, with subsequent verification of target gene expression via RT-qPCR. The levels of neuronal conduction proteins, including calmodulin-dependent protein kinase II (caMKII), CREB, and BDNF, were assessed through WB. Apoptosis was quantified by flow cytometry, while cell proliferation and viability were evaluated using the Cell Counting Kit-8 assay.

Results: The integration of transcriptomic and proteomic analyses identified 6079 co-expressed genes, among which 25 DEGs were significantly altered between the SZ group and healthy controls. Notably, haptoglobin (HP), lactotransferrin (LTF), and SERPING1 exhibited marked upregulation. KEGG pathway enrichment analysis implicated neuroactive ligand-receptor interaction pathways in disease pathogenesis. Clinical sample validation demonstrated elevated protein and mRNA levels of HP, LTF, and SERPING1 in the SZ group compared to controls. WB analysis of all clinical samples further corroborated the significant upregulation of SERPING1. In hippocampal CA1 neurons transfected with lentivirus, reduced SERPING1 expression was accompanied by increased levels of CaMKII, CREB, and BDNF, enhanced cell viability, and reduced apoptosis.

Conclusion: SERPING1 may suppress neural cell proliferation in SZ patients via modulation of the CaMKII-CREB-BDNF signaling pathway.

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综合转录组学和蛋白质组学分析显示，SERPING1通过CaMKII-CREB-BDNF通路抑制精神分裂症的神经元增殖。

背景：精神分裂症（SZ）是一种慢性和广泛的脑部疾病，具有复杂的病因和发病机制，目前尚未充分了解。尽管缺乏普遍认可的内表型，外周血单个核细胞（PBMCs）可作为研究与SZ相关的细胞内改变的稳健模型。目的：初步探讨SZ的潜在致病机制，并鉴定新的生物标志物。方法：对来自SZ患者的pbmc进行综合转录组学和蛋白质组学分析，以揭示差异表达基因（DEGs）和差异表达蛋白，同时绘制假定的疾病相关信号通路。通过western blot （WB）和实时荧光定量PCR （RT-qPCR）验证了关键发现。采用rnai慢病毒体外转染大鼠海马CA1神经元，随后通过RT-qPCR验证靶基因表达。神经传导蛋白水平，包括钙调素依赖性蛋白激酶II （caMKII）、CREB和BDNF，通过WB评估。用流式细胞术定量细胞凋亡，用细胞计数试剂盒-8测定细胞增殖和活力。结果：整合转录组学和蛋白质组学分析鉴定出6079个共表达基因，其中25个基因在SZ组与健康对照组之间发生了显著改变。值得注意的是，触珠蛋白（HP）、乳转铁蛋白（LTF）和SERPING1表现出明显的上调。KEGG通路富集分析提示神经活性配体-受体相互作用通路在疾病发病机制中。临床样本验证显示，与对照组相比，SZ组的HP、LTF和SERPING1蛋白和mRNA水平升高。所有临床样本的WB分析进一步证实了SERPING1的显著上调。在慢病毒转染的海马CA1神经元中，SERPING1表达的降低伴随着CaMKII、CREB和BDNF水平的升高，细胞活力增强，凋亡减少。结论：SERPING1可能通过调节CaMKII-CREB-BDNF信号通路抑制SZ患者神经细胞增殖。

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来源期刊

World Journal of Psychiatry PSYCHIATRY-

自引率

6.50%

发文量

110

期刊介绍： The World Journal of Psychiatry (WJP) is a high-quality, peer reviewed, open-access journal. The primary task of WJP is to rapidly publish high-quality original articles, reviews, editorials, and case reports in the field of psychiatry. In order to promote productive academic communication, the peer review process for the WJP is transparent; to this end, all published manuscripts are accompanied by the anonymized reviewers’ comments as well as the authors’ responses. The primary aims of the WJP are to improve diagnostic, therapeutic and preventive modalities and the skills of clinicians and to guide clinical practice in psychiatry.