O2.7. A NEUROPROTEOMICS-CENTERED APPROACH TO UNDERSTAND AND REVEAL BIOMARKERS TO SCHIZOPHRENIA

Abstract

Background Schizophrenia affects over 20 million people worldwide through a wide range of symptoms. As an incurable disorder, the disease management is normally based in antipsychotics, which may present severe side effects and does not work properly to half of the patients. This is mainly because we lack in understanding the molecular basis of the disease, impairing the development of new and more effective medication. Methods Here, we employed a neuroproteomics-centered approach to unravel molecular the underpinnings of schizophrenia as well as reveal protein biomarkers associated to antipsychotic effectiveness. For that, we have been using mass spectrometry-based proteomics to studying brain tissue collected postmortem from patients and mentally healthy controls, in vitro pre-clinical models such as cell lines and iPSC-derived cerebral organoids. Specific biological processes found in human samples which may be targeted by novel medication have been studied in pre-clinical models using genetic tools. Moreover, blood plasma collected in vivo from patients before and after antipsychotic medication (risperidone, olanzapine and quetiapine). Results At first, postmortem brain tissue proteomics from seven different brain regions led us to investigate in vitro the role of the above-mentioned biological processes in cultured oligodendrocytes treated with MK-801 and antipsychotics, to learn more about biochemical processes that may be involved in schizophrenia. iPSC-derived cerebral organoids, neurons and astrocytes were also investigated in terms of proteome dysregulations associated to the disease. Proteomic findings in postmortem brains and pre-clinical models have led us to investigate specific biological processes associated to the disease such as energy and mitochondrial metabolism, spliceosomal machinery, myelination and tripartite synapses. These may be targeted by novel medication. Additionally, we revealed blood plasma proteins, which are potential candidates to clinical implementation in the personalized choice of the correct antipsychotic to each patient. Discussion Neuroproteomics may be a powerful asset to reveal novel biological processes in the investigation of complex human disorders as schizophrenia. This has been contributing to knowledge that may lead to more effective medication and potential biomarkers for clinical use.