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

• Published in: Molecular psychiatry 2022-09, Vol.27 (9), p.3749-3759
• Main Authors: Ilieva, Mirolyuba, Aldana, Blanca Irene, Vinten, Kasper Tore, Hohmann, Sonja, Woofenden, Thomas William, Lukjanska, Renate, Waagepetersen, Helle S., Michel, Tanja Maria
• Format: Article
• Language: English
• Subjects: 13; 13/100; 14; 631/80; 692/699; 82; 82/16; 82/80; 96; 96/100; Autism; Autism Spectrum Disorder - genetics; Behavioral Sciences; Biological Phenomena; Biological Psychology; Cdc42 protein; Cell adhesion; Cell cycle; Cytoskeleton; Developmental stages; Drug development; Electron transport; Energy Metabolism; FOXO3 protein; Glycolysis; Heat shock proteins; Hsp27 protein; Humans; Medicine; Medicine & Public Health; Metabolism; Mitochondria; Neurodevelopmental disorders; Neurogenesis; Neurosciences; Organoids; Oxidative phosphorylation; Pharmacotherapy; Phenotype; Phenotypes; Phosphorylation; Protein kinase C; Protein turnover; Proteins; Proteome - genetics; Proteomes; Proteomics; Psychiatry; Rac1 protein; Transcription factors
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-022-01627-2

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.