Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes
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Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes. / Ilieva, Mirolyuba; Aldana, Blanca Irene; Vinten, Kasper Tore; Hohmann, Sonja; Woofenden, Thomas William; Lukjanska, Renate; Waagepetersen, Helle S.; Michel, Tanja Maria.
In: Molecular Psychiatry, Vol. 27, 2022, p. 3749–3759.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes
AU - Ilieva, Mirolyuba
AU - Aldana, Blanca Irene
AU - Vinten, Kasper Tore
AU - Hohmann, Sonja
AU - Woofenden, Thomas William
AU - Lukjanska, Renate
AU - Waagepetersen, Helle S.
AU - Michel, Tanja Maria
N1 - Funding Information: This work was supported by Psychiatry Research Foundation, Region Southern Denmark and Jascha Foundation. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41380-022-01627-2
DO - 10.1038/s41380-022-01627-2
M3 - Journal article
C2 - 35618886
AN - SCOPUS:85130722862
VL - 27
SP - 3749
EP - 3759
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
ER -
ID: 309269798