Plasma phosphoproteomic approaches to unravel new biomarkers in neuropsychiatric disorders

• Autor(a) principal: Monteiro, Eva Maria Ferro Abril
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/39545
• topic: Phosphoproteomic; Neuropsychiatric disorders; Schizoprenia; Bipolar; Mass spectrometry

Neuropsychiatric (NP) disorders have been a target of attention by many researchers in the last years. Their heterogeneity and complexity hamper an in-depth understanding of their pathophysiology. Moreover, the overlap of symptomatology hamper diagnosis, and so there is a need in discover biomarkers that allow a better stratification. Proteomics has been a strategy applied for biomarkers discovery. Phosphoproteomic shows a great potential in providing useful insights about the dynamics of biological processes, despite remaining poorly unexplored. As such, the goal of this exploratory study was to characterize the plasma phosphoproteome of NP patients. An MS-based phosphoproteomic approach was performed, using LC-MS/MS to identify and quantify proteins. Plasma samples from 69 patients and 15 controls were compared, aiming to characterize their phosphoproteome profiles. First, two clinical comparisons were performed: i) controls versus disease (CT vs D) and ii) schizophrenia/schizophreniform versus bipolar/other NPs (SCZF vs BDINT). Phosphoproteome profiles do not discriminate D group from the CT group, nor can be distinguished between SCZF and BDINT, through multivariate analysis (PLS-DA and PCA). Nevertheless, proteins and phosphopeptides were found significantly altered, through univariate analysis (Mann-Whitney test). In CT vs D, ALBU’s, C1orf74’s and IGG1’s significant phosphopeptides followed the tendency of the protein levels (ALBU downregulated in D; C1orf74 and IGG1 upregulated in D). Still, the phosphopeptide:protein ratio level was significant decreased and increased for ALBU and IGG1, respectively. The ALBU’s phosphopeptide showed potential as a candidate biomarker for NP disorder, with an area under the receiver operating curve value of 0.845. In SCZF vs BDINT, 4 phosphopeptides were significantly altered. ALBU’s, APOA1’s and GCN1’s phosphopeptides followed the protein levels tendency (ALBU downregulated in BDINT; APOA1 and GCN1 upregulated in BDINT). KNG1’s phosphopeptide was significantly increased in BDINT, despite no significantly differences at total protein level. The C1orf74’ phosphopeptide:protein ratio was significantly increased in BDINT, but no protein and phosphopeptide levels were found altered. Major associations of our results to literature findings can be done for ALBU and APOA1, already reported as altered in schizophrenia and bipolar disorder. Furthermore, IGG1 and KNG1 participate in inflammatory processes, being this state often described as a characteristic trait of NP profiles. This work allows to identify newly phosphorylation sites in phosphopeptides of interest. It also reveals the importance of studying phosphorylation, since some phosphorylated states were altered, which was not reflected in the total protein level. Nevertheless, the results still need to be validated in a larger cohort so that these potential biomarkers can aid in the diagnosis of NP disorders.