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Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia

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Abstract

Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world’s population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients, and therefore, do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls to assess possible alterations related to energy metabolism and mitochondrial function during neurodevelopment in the disorder. Our results revealed differentially expressed proteins in pathways related to mitochondrial function, cell cycle control, DNA repair and neuritogenesis and their possible implication in key process of neurodevelopment, such as neuronal differentiation and axonal guidance signaling. Moreover, functional analysis of NSCs revealed alterations in mitochondrial oxygen consumption in schizophrenia-derived cells and a tendency of higher levels of intracellular reactive oxygen species (ROS). Hence, this study shows evidence that alterations in important cellular processes are present during neurodevelopment and could be involved with the establishment of schizophrenia, as well as the phenotypic traits observed in adult patients.

Graphical abstract

Neural stem cells (NSCs) and neurons were derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients and controls. Proteomic analyses were performed on the enriched mitochondrial and nuclear fractions of NSCs and neurons. Whole-cell proteomic analysis was also performed in neurons. Our results revealed alteration in proteins related to mitochondrial function, cell cycle control, among others. We also performed energy pathway analysis and reactive oxygen species (ROS) analysis of NSCs, which revealed alterations in mitochondrial oxygen consumption and a tendency of higher levels of intracellular ROS in schizophrenia-derived cells.

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Availability of data and materials

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [84] partner repository with the dataset identifier PXD021976 and https://doi.org/10.6019/PXD021976.

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Acknowledgements

We thank Gabriela Lopes Vitória for her excellent support related to stem cell generation and culture and Ludmila S. S. Bastos for cell bank expansion. We also thank Mariana Fioramonte for her support with the mass spectrometry analysis. We thank the São Paulo Research Foundation—FAPESP (grant numbers 2016/04912-2, 2018/14666-4, 2014/21035-0, 2015/15626-8, 2017/25588-1 and 2019/00098-7); the Brazilian National Council for Scientific and Technological Development—CNPq and the Foundation for Research Support in the State of Rio de Janeiro (FAPERJ) for funding this work.

Funding

Conselho Nacional de Desenvolvimento Científico e Tecnológico, 2018/01410-1, Daniel Martins de-Souza, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro.

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Authors and Affiliations

  1. Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil

    Giuliana S. Zuccoli, Juliana M. Nascimento & Daniel Martins-de-Souza

  2. D’Or Institute for Research and Education (IDOR), São Paulo, Brazil

    Juliana M. Nascimento, Stevens K. Rehen & Daniel Martins-de-Souza

  3. Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil

    Pedro M. Moraes-Vieira

  4. Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP, 13083-862, Brazil

    Pedro M. Moraes-Vieira & Daniel Martins-de-Souza

  5. Obesity and Comorbidities Research Center (OCRC), University of Campinas, São Paulo, Brazil

    Pedro M. Moraes-Vieira

  6. Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil

    Stevens K. Rehen

  7. Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, Brazil

    Daniel Martins-de-Souza

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  1. Giuliana S. Zuccoli
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Contributions

GSZ, JMN, SKR and DMS contributed to the conceptualization and design of the study. GSZ performed the experiments and analyzed the data. PMMV contributed to the design of the metabolic analysis. GSZ wrote the first draft of the manuscript. GSZ, JMN and DMS reviewed the final manuscript. All the authors approved the final version of the manuscript.

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Correspondence to Daniel Martins-de-Souza.

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Zuccoli, G.S., Nascimento, J.M., Moraes-Vieira, P.M. et al. Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia. Eur Arch Psychiatry Clin Neurosci 273, 1649–1664 (2023). https://doi.org/10.1007/s00406-023-01605-x

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