Cellular prion protein (PrPC) triggers an Arc response and activates phospholipase Cɣ1 in iPSC-derived human neurons

Synapse loss and neuronal hyperactivity occur early in Alzheimer’s disease before pronounced neuronal loss and hypoactivity are evident, yet the mechanisms driving neuronal hyperactivity are poorly understood. Synapse loss is an early neuropathological feature of prion disease, and the onset of clinical signs correlates with reduced synaptic proteins. Here we identify an increase in the immediate early gene, Arc/Arg3.1, in the brain of patients with prion disease (sporadic and familial), suggestive of neuronal hyperactivity. To investigate the early signaling events initiated by prion aggregates (PrP^Sc), we stimulated PrP^C in human iPSC-derived excitatory neurons (iNs) with a PrP^Sc-mimetic (anti-PrP antibody, POM1), which recapitulated the Arc/Arg3.1 response within two hours. To identify the signaling cascade driving the Arc elevation, we tested POM1-treated iNs using a phosphokinase array, which revealed decreased phosphorylated EGF receptor (Y1086) (pEGFR) and increased phosphorylated phospholipase C (PLC)-γ1 (Y783) (pPLC-γ1), suggestive of PLC-γ1-activation. Similarly, pEGFR was decreased and pPLC-γ1 was increased in the cerebral cortex of prion-infected mice at the onset of clinical symptoms. PLCγ1 triggers calcium release from the ER and may underlie the increase in Arc. Pharmacological inhibition of EGFR prevented the Arc response to POM1. Thus, PrP^C ligands can induce an acute PLC-γ1 intracellular signaling cascade together with an Arc response. Understanding the signaling pathways triggered by PrP^C may lead to novel therapeutic targets for prion disease.