A de novo Missense Mutation in PPP2R5D Alters Dopamine Pathways and Morphology of iPSC-derived Midbrain Neurons

Induced pluripotent stem cell (iPSC) models of neurodevelopmental disorders (NDDs) have promoted an understanding of commonalities and differences within or across patient populations by revealing the underlying molecular and cellular mechanisms contributing to disease pathology. Here, we focus on developing a human model for PPP2R5D-related NDD, called Jordan syndrome, which has been linked to Early-Onset Parkinson’s Disease (EOPD). This disease model includes patient-derived induced pluripotent stem cells (iPSCs) which were differentiated into neural stem cells (NSCs) and subsequently specified into a midbrain neural stem cell and neuronal state. We sought to understand the underlying molecular and cellular phenotypes across multiple cell states and neuronal subtypes in order to gain insight into Jordan syndrome pathology. Our work revealed that iPSC-derived midbrain neurons from Jordan syndrome patients display significant differences in dopamine-associated pathways and neuronal architecture. To develop a better understanding of the molecular consequence of mutant PPP2R5D pathology, RNA sequencing was performed across the four cell states of our disease model (iPSC, NSC, midbrain NSC and midbrain neuron) for isogenic and PPP2R5D E198K lines.