Proteomic analysis of peripheral blood mononuclear cells in first episode psychosis – Protein and peptide-centered approaches to elucidate potential diagnostic biomarkers

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.