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Modeling Fragile X Syndrome using human brain organoids

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Technical Report,01 Mar 2019,29 Feb 2020

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Emory University Atlanta United States

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Fragile X syndrome FXS is the most common inherited form or intellectual disability and a leading genetic cause of autism spectrum disorder ASD. An expansion of a CGG repeat in the 5 untranslated region of the gene leads to hypermethylation of the gene, and the gene product, FMRP, is no longer made. When FMRP is not made, other genes are improperly regulated, and many of these genes are autism-linked genes. In this project, we have used human-induced pluripotent stem cells iPSCs from FXS patients to create human forebrain organoids to study the alterations that occur in human brains when FMRP is absent. We have identified that loss of FMRP in FXS organoids leads to premature differentiation of neural progenitor cells. Further, when we studied the fate of these neurons after differentiation, we identified a significant reduction in GABAergic neurons in the FXS organoids. We also identified an increase in the density of synaptic boutons in the FXS neurons and an increase in the action potential firing frequency, suggesting the hyperexcitability of FXS neurons. When we compared the mRNA targets of FMRP in the FXS organoid to the FMRP targets in mouse cortex, we found that FMRP targets are enriched in neuronal pathways. In particular, the human FMRP targets were significantly enriched among ASD-associated genes. We have also performed RNA-seq analysis of FXS organoids and mouse brains. The differentially expressed genes identified in from FXS organoids were enriched for pathways related to neurodevelopment. These results together show the feasibility of using FXS organoids as a human-specific preclinical model and a resource for studying the molecular pathogenesis of FXS.

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  • Medicine and Medical Research

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