What Does Proteomics Tell Us About Schizophrenia?

Abstract

Background: In the last decade, schizophrenia (SCZ) biomarkers have been searched by genotyping techniques, genome wide association studies and large-scale transcriptome analyses. Proteome analysis has emerged in this context as a promising strategy. Initially, the search for protein biomarkers of SCZ in human brain tissue via proteomics aimed primarily to provide information on the risk for the disease, to contribute to the early diagnosis and to the prediction of the therapeutic response. After several proteomic studies conducted in several brain regions, it became clear that the secondary objective of such type of research which were to provide detailed information about the pathophysiology of the disease and to further confirm the importance of certain pathways have become the main and more useful findings, although potential biomarkers candidates have also been pointed out as primarily expected. Methods: We have studied the post-mortem proteomes of the dorsolateral prefrontal cortex, anterior temporal lobe, Wernicke's area, anterior cingulate cortex, and thalamus from SCZ patients comparing to mentally healthy controls using different proteomic methodologies such as two-dimensional gel electrophoresis and shotgun mass spectrometry. Results: We have found the most often alterations in energy metabolism, oligodendrocyte-function and myelinization, calcium homeostasis and cytoskeleton.Moreover, we have revealed the differential expression of a number of hypothetical or putative proteins, which might be interesting targets to further studies considering their underlie information. Several protein biomarker candidates such as myelin basic protein and myelin oligodendrocyte protein were evaluated and validated by western blot in some of the described brain regions as well as in cerebrospinal fluid from a separate set of samples. A number of glycolysis enzymes have been found differentially expressed in the analyzed brain regions, what have led us to quantify the levels of pyruvate and NADPH in thalamus, which indeed were found altered. Conclusion: The recurrent identification and validation of inter-related protein clusters, determined in different samples by different proteomic approaches not only strongly reinforces the putative involvement of certain pathways in SCZ, but also reveal new potential biomarkers and paves the way to the development of new therapeutic strategies in order to contribute for reducing the social and cognitive consequences of the disease.