CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
Faculty of Medicine of the University of Coimbra, University of Coimbra, Portugal; Psychiatry Department, Centro Hospitalar e Universitário de Coimbra, Portugal; CIBIT - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Portugal.
J Proteomics. 2024 Oct 30;309:105296. doi: 10.1016/j.jprot.2024.105296. Epub 2024 Aug 30.
Diagnosing patients suffering from psychotic disorders is far from being achieved with molecular support, despite all the efforts to study these disorders from different perspectives. Characterizing the proteome of easily obtainable blood specimens, such as the peripheral blood mononuclear cells (PBMCs), has particular interest in biomarker discovery and generating pathophysiological knowledge. This approach has been explored in psychiatry, and while generating valuable information, it has not translated into meaningful biomarker discovery. In this project, we report the proof-of-concept of a methodology that aims to explore further information obtained with classical proteomics approaches that is easily overlooked. PBMC samples from first-episode psychosis and control subjects were subjected to a SWATH-MS approach, and the classical protein relative quantification was performed, where 389 proteins were found to be important to distinguish the two groups. Individual analysis of the quantified peptides was also performed, highlighting peptides of unchanged proteins that were significantly altered. With the combination of protein- and peptide-centered proteomics approaches, it is possible to highlight that information about proteoforms, namely regulation at the peptide level possibly due to post-translational modifications, is routinely overlooked and that its diagnostic potential should be further explored. SIGNIFICANCE: Our exploratory findings highlight the potential of MS-based proteomics strategies, combining protein- and peptide-centered approaches, to aid clinical decision-making in first-episode psychosis, helping to establish early biomarkers for schizophrenia and other psychotic disorders. Particularly, the less popular peptide-centered approach allows the identification/measurement of overlooked modulated peptides that may have potential biomarker characteristics. The application in parallel of protein- and peptide-centered strategies is transversal to research of other diseases, potentially allowing a more comprehensive characterization of the metabolic/pathophysiological alterations related to a specific disease.
尽管从不同角度研究这些疾病的努力从未停止，但目前仍无法仅通过分子手段来诊断患有精神病的患者。在外周血单核细胞（peripheral blood mononuclear cells，PBMCs）等易于获取的血液标本中鉴定蛋白质组具有发现生物标志物和产生病理生理学知识的特殊意义。这种方法已经在精神病学中得到了探索，尽管产生了有价值的信息，但并没有转化为有意义的生物标志物发现。在本项目中，我们报告了一种方法的概念验证，该方法旨在进一步探索经典蛋白质组学方法获得的容易被忽视的信息。对首发精神病患者和对照者的 PBMC 样本进行了 SWATH-MS 分析，并进行了经典蛋白质相对定量，结果发现 389 种蛋白质对于区分两组非常重要。还对定量肽进行了单独分析，突出显示了明显改变的不变蛋白质的肽。通过结合基于蛋白质和肽的蛋白质组学方法，可以突出表明有关蛋白质形式的信息，即肽水平的调节（可能是由于翻译后修饰）通常被忽略，并且应该进一步探索其诊断潜力。意义：我们的探索性发现强调了基于 MS 的蛋白质组学策略的潜力，该策略结合了基于蛋白质和肽的方法，有助于首发精神病的临床决策，有助于建立精神分裂症和其他精神病的早期生物标志物。特别地，不太流行的基于肽的方法允许鉴定/测量可能具有潜在生物标志物特征的被忽视的调节肽。蛋白质和肽中心策略的并行应用贯穿于其他疾病的研究，有可能更全面地描述与特定疾病相关的代谢/病理生理改变。
