Proteomic signatures of schizophrenia-sourced iPSC-derived neural cells and brain organoids are similar to patients' postmortem brains

Juliana Minardi Nascimento, Verônica M. Saia-Cereda, Giuliana S. Zuccoli, Guilherme Reis-de-Oliveira, Victor Corasolla Carregari, Bradley J. Smith, Stevens K. Rehen, Daniel Martins-de-Souza

Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding the timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease. Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors (NPCs), early neurons, and brain organoids in comparison to healthy individuals. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis, we found multiple dysregulated proteins since NPCs, modified, and disrupted the 21DIV neuronal differentiation, and cerebral organoids. Our experimental methods have shown impairments in pathways never before found in patient-derived induced pluripotent stem cells studies, such as spliceosomes and amino acid metabolism; but also, those such as axonal guidance and synaptogenesis, in line with postmortem tissue studies of schizophrenia patients. In conclusion, here we provide comprehensive, large-scale, protein-level data of different neural cell models that may uncover early events in brain development, underlying several of the mechanisms within the origins of schizophrenia.