Unraveling the Molecular Landscape of SCN1A Gene Knockout\nin Cerebral Organoids: A Multiomics Approach Utilizing Proteomics,\nLipidomics, and Transcriptomics

This study investigates\nthe impact of sodium channel protein type\n1 subunit alpha (SCN1A) gene knockout (SCN1A KO) on brain development\nand function using cerebral organoids coupled with a multiomics approach.\nFrom comprehensive omics analyses, we found that SCN1A KO organoids\nexhibit decreased growth, dysregulated neurotransmitter levels, and\naltered lipidomic, proteomic, and transcriptomic profiles compared\nto controls under matrix-free differentiation conditions. Neurochemical\nanalysis reveals reduced levels of key neurotransmitters, and lipidomic\nanalysis highlights changes in ether phospholipids and sphingomyelin.\nFurthermore, quantitative profiling of the SCN1A KO organoid proteome\nshows perturbations in cholesterol metabolism and sodium ion transportation,\npotentially affecting synaptic transmission. These findings suggest\ndysregulation of cholesterol metabolism and sodium ion transport,\nwith implications for synaptic transmission. Overall, these insights\nshed light on the molecular mechanisms underlying SCN1A-associated\ndisorders, such as Dravet syndrome, and offer potential avenues for\ntherapeutic intervention.