Abstract

The most common subtype of genetic prion disease is caused by the E200K mutation of the prion protein. We have obtained samples from 22 members of a multi-generational Israeli family harboring this mutation, and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. Whole-exome sequencing was performed on all individuals. A comparison of neurons derived from E200K iPSCs to those from non-carriers revealed the presence of several disease-relevant phenotypes. Neurons from E200K carriers were found to contain thioflavin S-positive accumulations of PrP in their cell bodies. In addition, these neurons displayed disruptions of NMDA receptor/PSD95 co-localization at postsynaptic sites. Our study shows that iPSC-derived neurons, which express physiologically relevant levels of mutant PrP in a human neuronal context, can model certain aspects of human prion disease, offering a powerful platform for investigating pathological mechanisms and testing potential therapeutics.