PrPC-facilitated cell signaling activates phospholipase Cɣ1 and triggers an Arc/Arg3.1 response in mouse neurons and human iPSC-derived neurons

We recently found evidence of neuronal hyperactivity and synaptic loss in prion-infected mice. Herein we identified increased Arc/Arg3.1 in patients with prion disease, suggesting heightened neuronal activity also occurs in human prion-affected brain.

To determine the signaling events initiated by prion aggregates (PrPSc), we developed a disease model in which human iPSC-derived excitatory neurons are stimulated with a PrPSc-mimetic antibody that binds cellular prion protein (PrPC). Within two hours, we detected an Arc/Arg3.1 response together with transcriptomic changes previously reported in prion-infected mice. We identified altered phosphorylation of PLC-γ1, ERK1/2, and EGFR as PrPC-triggered cell signaling events that accompany the Arc/Arg3.1.