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Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes

Molecular Psychiatry volume 27, pages 3749–3759 (2022)Cite this article

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Abstract

The way in which brain morphology and proteome are remodeled during embryonal development, and how they are linked to the cellular metabolism, could be a key for elucidating the pathological mechanisms of certain neurodevelopmental disorders. Cerebral organoids derived from autism spectrum disorder (ASD) patients were generated to capture critical time-points in the neuronal development, and metabolism and protein expression were investigated. The early stages of development, when neurogenesis commences (day in vitro 39), appeared to be a critical timepoint in pathogenesis. In the first month of development, increased size in ASD-derived organoids were detected in comparison to the controls. The size of the organoids correlates with the number of proliferating cells (Ki-67 positive cells). A significant difference in energy metabolism and proteome phenotype was also observed in ASD organoids at this time point, specifically, prevalence of glycolysis over oxidative phosphorylation, decreased ATP production and mitochondrial respiratory chain activity, differently expressed cell adhesion proteins, cell cycle (spindle formation), cytoskeleton, and several transcription factors. Finally, ASD patients and controls derived organoids were clustered based on a differential expression of ten proteins—heat shock protein 27 (hsp27) phospho Ser 15, Pyk (FAK2), Elk-1, Rac1/cdc42, S6 ribosomal protein phospho Ser 240/Ser 244, Ha-ras, mTOR (FRAP) phospho Ser 2448, PKCα, FoxO3a, Src family phospho Tyr 416—at day 39 which could be defined as potential biomarkers and further investigated for potential drug development.

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Fig. 1: Immunocytochemistry of brain organoids demonstrating the formation of cortical layering and variety of cellular populations.
Fig. 2: Glucose metabolism in cerebral organoids derived from ASD patients and controls.
Fig. 3: Hierarchical clustering.

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Acknowledgements

This work was supported by Psychiatry Research Foundation, Region Southern Denmark and Jascha Foundation.

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  1. Mirolyuba Ilieva

    Present address: Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen SV, Denmark

Authors and Affiliations

  1. Department of Psychiatry, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Mirolyuba Ilieva, Sonja Hohmann, Renate Lukjanska & Tanja Maria Michel

  2. Psychiatry in the Region of Southern Denmark, Odense University Hospital, Odense, Denmark

    Mirolyuba Ilieva, Sonja Hohmann, Renate Lukjanska & Tanja Maria Michel

  3. Neurometabolism Research Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Blanca Irene Aldana, Kasper Tore Vinten, Thomas William Woofenden & Helle S. Waagepetersen

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Contributions

MI, BIA, HSW, TMM conceived and designed the experiments. MI, BIA, KTV, SH, TWW, and RL performed the experiments. MI, BIA, KTV, SH, TWW, and RL analyzed the data, generated figures, and wrote the manuscript. MI and TMM directed and supervised the project. All authors have read and agreed to the published version of the manuscript.

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Ilieva, M., Aldana, B.I., Vinten, K.T. et al. Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes. Mol Psychiatry 27, 3749–3759 (2022). https://doi.org/10.1038/s41380-022-01627-2

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  • DOI: https://doi.org/10.1038/s41380-022-01627-2

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