NMDA receptor misalignment in iPSC-derived neurons from a multi-generational family with inherited Creutzfeldt-Jakob disease

Author:

Le Nhat T.T.,Mercer Robert C.C.,Gojanovich Aldana D.,Anane Alice,Park Seonmi,Wu Bei,Bawa Pushpinder S.,Mostoslavsky Gustavo,Harris David A.,

Abstract

SummaryThe 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.

Publisher

Cold Spring Harbor Laboratory

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