Jordan's Syndrome (JS) is a neurodevelopmental disorder caused by de novo mutations in protein phosphatase 2 regulatory subunit B56delta (PPP2R5D). PPP2R5D encodes for B56delta, one of the regulatory subunits of protein phosphatase 2A (PP2A). PP2A is a heterotrimeric protein serine/threonine phosphatase that is highly expressed in the brain and the liver. To understand how the mutations affect neuronal cells, we developed cerebral cortical-like organoids from an engineered allele series of the most common JS mutations to characterize the physiological changes throughout different stages of neurodevelopment. Organoids were assessed for transcriptomic, protein, and electrophysiological changes utilizing bulk RNA sequencing, immunocytochemistry, Western Blot, and high-density MicroElectrode Array. The results identify differentially expressed genes and translated proteins, potential neuronal substrates, and significant electrophysiological signatures that suggest mutations in 2R5D lead to variant-specific dysfunction of PP2A. Overexpression of PPP2R5D through AAV transduction rescued several phenotypes, suggesting different pathogenetic etiology underneath. Our findings successfully characterized cerebral cortical-like organoids in JS cell lines and demonstrated its potential as a model for studying neurodevelopmental disorder and for screening therapeutic approaches.
Du, Y., Singh, M., Patil, M., Villeagas, I., Portillo, A., Shang, K., Ben-Shalom, R., Halmai, J., Fink, K.
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