Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease

Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrPC). Why these mutations are pathogenic, and how they alter the properties of PrPC are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrPSc, the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrPC may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics. •iPSC library from a family harboring the CJD causing E200K mutation of PrP•Robust cortical neuronal differentiation with no development of pathological PrP•E200K PrP-expressing neurons have an abnormal postsynaptic site In this article, Mostoslavsky, Harris, and colleagues present a large library of induced pluripotent stem cells (iPSCs) obtained from members of a multi-generational, Israeli family who harbor the E200K mutation in the prion protein, which causes genetic Creutzfeldt-Jakob disease. They differentiated the iPSCs into cortical neurons, and, despite the absence of pathological PrP formation, they documented an abnormal postsynaptic site. This collection will enable the exploration of key questions in the pathogenesis of genetic prion disease.