UC San Diego

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 (PrP^Sc), we developed a disease model in which human iPSC-derived excitatory neurons are stimulated with a PrP^Sc-mimetic antibody, POM1, that binds cellular prion protein (PrP^C). 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 PrP^C-triggered cell signaling events. These results suggest that PrP^C ligands, including PrP^Sc, trigger rapid signaling events linked to neuronal hyperactivity in human neurons, and indicate PLC-γ1 as a potential therapeutic target.