Summary
Familial Creutzfeldt-Jakob disease (fCJD) caused by the E200K mutation of the prion protein (PrP) is the most common subtype of genetic prion disease. We have generated a library of human induced pluripotent stem cells (iPSCs) derived from a family with the E200K mutation, comprised of 11 carriers and 11 non-carriers. A comparison of neurons derived from E200K iPSCs to those from non-carriers revealed the presence of several disease-relevant phenotypes. Although traditional proteinase K resistant, detergent-insoluble, and seed-competent PrP was not observed, neurons derived from E200K carriers were found to contain thioflavin S positive PrP puncta. At the postsynaptic site, the co-localization of N-Methyl-D-aspartic acid receptors and post synaptic density 95 colocalization was disrupted in neurons expressing E200K PrP. Our study shows that iPSC-derived neurons, which express endogenous 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.
Competing Interest Statement
The authors have declared no competing interest.