Abstract
Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrP(C)). Why these mutations are pathogenic, and how they alter the properties of PrP(C) 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 PrP(Sc), the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrP(C) 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.