Accumulation of misfolded prion protein overactivates the unfolded protein response (UPR) and results in a cell-wide shutdown of protein translation and consequent synaptic dysfunction and cell death. The kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase) is a key component in the UPR, and oral administration of a PERK inhibitor in a mouse model of prion disease, either before or after manifestation of symptoms, attenuated disease progression. PERK inhibitors function downstream of prion replication and thus have therapeutic potential in neurodegenerative diseases that involve UPR activation.