Exploring protein post-translational modifications in schizophrenia postmortem brains

• Grant number: 23/04767-6
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 05, 2023
• End date: July 04, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Daniel Martins-de-Souza
• Grantee: Victor Corasolla Carregari
• Supervisor: Martin R. Larsen
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Southern Denmark (SDU), Denmark
• Associated to the scholarship: 19/05155-9 - The role of the glycoproteome and phosphoproteome during neuronal differentiation in schizophrenia, BP.PD

Abstract

Schizophrenia is a debilitating mental disorder, which affects approximately 1% of the world population, bringing a significant social and economic burden. Schizophrenia is a multifactorial disease associated with several gene/protein alterations that are highly influenced by environmental factors. Disease symptoms generally manifest in young adults when the neurodevelopment is at its end. Although many studies have been conducted to understand the origin of schizophrenia, little is known about the molecular mechanisms involved in the early and late disease development. One of the most important regulatory mechanisms to a cellular phenotype is post-translational modifications (PTMs), a diverse class of changes that proteins can undergo to change various physical and functional properties. It is known that PTMs such as glycosylation and phosphorylation play a key role in brain development, and since schizophrenia is a disorder that starts during neuronal development, PTM dysregulation may lead to defects in the differentiation and migration process of the neural cells, resulting in future impairment in neuronal communications. Many others PTMs are possibly related to the development or to miss communication of the neuronal synapse but they are still poorly explored. The aim of this project is to perform glycoproteomic, phosphoproteomic, and cysteine modification analyses of the total protein extract from postmortem brain tissue derived from patients with schizophrenia and control individuals. An in silico analysis will then be performed to identify common changes and affected pathways that are also present in our dataset of the PTMs profile of neuron and astrocytes derived from hiPSCs with a schizophrenia genetic background, analyzed at different time points during the developmental process (obtained in the original project) and at the end of the disease. For the first time, cysteine modifications in postmortem brain tissue from patients with schizophrenia will be analyzed, expanding the possibilities of identifying specific signaling modulations that lead to the malfunction of synaptic transmissions. The field of PTMomics is still expanding and developing, with several modifications already implicated in the etiology and treatment of schizophrenia. However, much remains to be uncovered due to the vast number of modifications that occur on proteins. This project aims to increase our understanding of the role of these PTMs in schizophrenia and the dysfunctions induced by the disorder. (AU)