Ubiquitin-proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia

Author(s)

Seabra, Gabriela ^[1] ; de Almeida, Valeria ^[1] ; Reis-de-Oliveira, Guilherme ^[1] ; Crunfli, Fernanda ^[1] ; Leao Marcelo Antunes, Andre Saraiva ^[1] ; Martins-de-Souza, Daniel ^{[1, 2, 3]}

Affiliation

^[1] Univ Campinas UNICAMP, Inst Biol, Dept Biochem & Tissue Biol, Lab Neuroprote, Rua Monteiro Lobato 255, BR-13083862 Campinas, SP - Brazil

^[2] DOr Inst Res & Educ IDOR, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Expt Med Res Cluster EMRC, Campinas, SP - Brazil

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1 JUL 28 2020.
• Web of Science Citations: 0

Abstract

Schizophrenia is a chronic, severe and disabling psychiatric disorder, whose treatment is based on psychosocial interventions and the use of antipsychotic drugs. While the effects of these drugs are well elucidated in neuronal cells, they are still not so clear in oligodendrocytes, which play a vital role in schizophrenia. Thus, we aimed to characterize biochemical profiles by proteomic analyses of human oligodendrocytes (MO3.13) which were matured using a protocol we developed and treated with either haloperidol (a typical antipsychotic), clozapine (an atypical antipsychotic) or a clozapine+d-serine co-treatment, which has emerged lately as an alternative type of treatment. This was accomplished by employing shotgun proteomics, using nanoESI-LC-MS/MS label-free quantitation. Proteomic analysis revealed biochemical pathways commonly affected by all tested antipsychotics were mainly associated to ubiquitination, proteasome degradation, lipid metabolism and DNA damage repair. Clozapine and haloperidol treatments also affected proteins involved with the actin cytoskeleton and with EIF2 signaling. In turn, metabolic processes, especially the metabolism of nitrogenous compounds, were a predominant target of modulation of clozapine+d-serine treatment. In this context, we seek to contribute to the understanding of the biochemical and molecular mechanisms involved in the action of antipsychotics on oligodendrocytes, along with their possible implications in schizophrenia. (AU)

• FAPESP's process: 19/22398-2 - The role of cholesterol synthesis in the mode of action of clozapine in schizophrenia models
• Grantee: Fernanda Crunfli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/25588-1 - From the basic understanding to clinical biomarkers to schizophrenia: a neuroproteomics-centered multidisciplinary study
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/10068-4 - Multi-User Equipment approved in grant 13/08711-3: mass spectrometer waters SYNAPT G2-Si HDMS + nanoACQUITY UPLC
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 17/18242-1 - Biochemical pathways affected by cannabinoid drugs of human oligodendrocytes
• Grantee: Valéria de Almeida
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/03271-1 - Proteome modulation by cannabinoid drugs in human oligodendrocytes
• Grantee: Gabriela Seabra
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 19/00098-7 - Multi-User Equipment approved in grant 2017/25588-1: cromatógrafo Acquity UPLC I-Class
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 18/03673-0 - Biochemical effects of cannabinoids on oligodendrocytes: implications for schizophrenia
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Regular Research Grants