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

Synapse loss is an early feature of prion disease, yet the underlying drivers are poorly understood. 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 the 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, POM1, that binds cellular prion protein (PrPC). Within 2 h of POM1 exposure, 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 additional PrPC-triggered cell signaling events. These results suggest that PrPC ligands, including PrPSc, trigger rapid signaling events linked to neuronal hyperactivity in human neurons, and indicate PLC-γ1 as a potential therapeutic target.