Abstract
Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) [1st sample set: 30 SCZ and 30 control subjects (CON)]. Differentially expressed protein spots were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.
Highlights
Schizophrenia (SCZ) is a chronic and disabling mental disorder, typically occurring after puberty, with a lifetime prevalence of ~1% in the global population
A total of 1 174 protein spots were identified on typical lymphoblastoid cell lines (LCLs) gels [SCZ 1 102.8 (s.d. = 13.3); control subjects (CON) 1 102.6 (s.d. = 16.2)], with 20 spots being differentially expressed between SCZ-LCL and CON-LCL, of which seven spots were increased while 13 spots were decreased in SCZ-LCL (Table 1)
MX1 and IGHM were significantly up-regulated in SCZ-LCL, while HSPA4L, GLRX3, UROD, MAPRE1, TBCB, and GART were significantly down-regulated in the 1st sample set
Summary
Schizophrenia (SCZ) is a chronic and disabling mental disorder, typically occurring after puberty, with a lifetime prevalence of ~1% in the global population. SCZ is a disease of the central nervous system (CNS) and investigations of brain samples will no doubt provide meaningful information, it is very difficult to obtain brain biopsy samples from patients. Post-mortem brains have been investigated, these samples are affected by various confounding factors related to the age at death, medication, cause of death, agonal state, post-mortem interval, and brain pH4. Fresh blood is useful for screening peripheral biomarkers, it is affected by various confounding factors such as health condition, diet, medication, smoking, and circadian rhythms[3]. As well as microarray or generation sequencing (NGS)-based transcriptome studies, have been demonstrated to be useful for screening molecular expression changes to obtain novel insights into disease[7]. Proteomics could provide molecular biology based diagnostic tools (biomarkers) for monitoring symptom severity, treatment responses, and predicting progression
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