• brain organoids
• Induced pluripotent stem cells (iPSCs)
• mass spectrometry
• metabolomics
• Trisomy 21

Trisomy 21 (Ts21), or Down syndrome (DS), is the leading genetic cause of developmental delay and intellectual disability, caused by the triplication of chromosome 21 and resulting in gene overexpression. This overexpression affects multiple organ systems, including the central nervous system. Research into DS neuropathology has traditionally relied on postmortem human tissue and trisomic mouse models. Recent advances have been made with induced pluripotent stem cells (iPSCs) and their 3D organoid models, which mimic human organ architecture and physiology.

Our study aims to explore metabolic dysfunction at the neuronal level using iPSC-derived cortical organoids from a mosaic DS patient, comparing trisomy 21 cells to isogenic controls. Notable differences in media color and pH in Ts21 cultures suggest metabolic alterations, supported by previous findings of altered mitochondrial gene expression in DS. We generated cortical organoids from Ts21 iPSCs and their controls and analyzed their metabolome at various developmental stages using high-performance liquid chromatography-mass spectrometry (HPLC-MS), including untargeted metabolomics and lipidomics. This research will provide insights into metabolic dysregulation in DS and contribute to understanding biochemical dysfunction, potentially advancing knowledge on neuronal impairments and intellectual disorders associated with DS.