Aline Santana

Employing proteomics to unravel the molecular effects of antipsychotics and their role in schizophrenia.

Schizophrenia is an incurable neuropsychiatric disorder managed mostly by treatment of the patients with antipsychotics. However, the efficacy of these drugs has remained only low to moderate despite intensive research efforts since the early 1950s when chlorpromazine, the first antipsychotic, was synthesized. In addition, antipsychotic treatment can produce often undesired severe side effects in the patients and addressing these remains a large unmet clinical need. One of the reasons for the low effectiveness of these drugs is the limited knowledge about the molecular mechanisms of schizophrenia, which impairs the development of new and more effective treatments. Recently, proteomic studies of clinical and preclinical samples have identified changes in the levels of specific proteins in response to antipsychotic treatment, which have converged on molecular pathways such as cell communication and signaling, inflammation and cellular growth, and maintenance. The findings of these studies are summarized and discussed in this review and we suggest that this provides validation of proteomics as a useful tool for mining drug mechanisms of action and potentially for pinpointing novel molecular targets that may enable development of more effective medications.

Proteomics and molecular tools for unveiling missing links in the biochemical understanding of schizophrenia

Psychiatric disorders are one of the biggest burdens to society, with significant personal and economical costs. Schizophrenia (SCZ), among them, is still poorly understood, and its molecular characterization is crucial to improve patients’ diagnosis and treatment. The combination of genetic, biochemical, and environmental factors leads to systemic alterations, which are yet to be fully comprehended. Thus, understanding those missing links by connecting some molecular reports of SCZ is essential. From postmortem brain to animal models and cell culture, new tools are emerging, including recent advances in proteomics, and there is a need to apply them to solve these problems. Here, we review some of those features, mainly related to where proteomics could help, and discuss whether those new technologies could and should be applied to psychiatric disorder studies.

The Nuclear Proteome of White and Gray Matter from Schizophrenia Postmortem Brains

Schizophrenia (SCZ) is a serious neuropsychiatric disorder that manifests through several symptoms from early adulthood. Numerous studies over the last decades have led to significant advances in increasing our understanding of the factors involved in SCZ. For example, mass spectrometry-based proteomic analysis has provided important insights by uncovering protein dysfunctions inherent to SCZ. Here, we present a comprehensive analysis of the nuclear proteome of postmortem brain tissues from corpus callosum (CC) and anterior temporal lobe (ATL). We show an overview of the role of deregulated nuclear proteins in these two main regions of the brain: the first, mostly composed of glial cells and axons of neurons, and the second, represented mainly by neuronal cell bodies. These samples were collected from SCZ patients in an attempt to characterize the role of the nucleus in the disease process. With the ATL nucleus enrichment, we found 224 proteins present at different levels, and 76 of these were nuclear proteins. In the CC analysis, we identified 119 present at different levels, and 24 of these were nuclear proteins. The differentially expressed nuclear proteins of ATL are mainly associated with the spliceosome, whereas those of the CC region are associated with calcium/calmodulin signaling.

Ion mobility-enhanced data-independent acquisitions enable a deep proteomic landscape of oligodendrocytes

Oligodendrocytes are a type of neuroglia that provide trophic support and insulation to axons in the central nervous system. The genesis and maturation of oligodendrocytes are essential processes for myelination and the course of CNS development. Using ion mobility‐enhanced, data‐independent acquisitions and 2D‐nanoUPLC fractionation operating at nanoscale flow rates, we established a comprehensive data set of proteins expressed by the human oligodendroglia cell line MO3.13. The final dataset incorporating all fractions comprised 223 531 identified peptides assigned to 10 390 protein hits, an improvement of 4.5 times on identified proteins described previously by our group using the same cell line. Identified proteins play pivotal roles in many biological processes such as cell growth and development and energy metabolism, providing a rich resource for future studies on oligodendrocyte development, myelination, axonal support, and the regulation of such process. Our results can help further studies that use MO3.13 cells as a tool of investigation, not only in relation to oligodendrocyte maturation, but also to diseases that have oligodendrocytes as key players. All MS data have been deposited in the ProteomeXchange with identifier PXD004696.