Targeting the endoplasmic reticulum in prion disease treatment: breakthroughs and challenges

Prion diseases are infectious, predominantly fatal neurodegenerative diseases characterized by abnormal prion protein (PrP) accumulation and neuronal loss. Studies on experimental animal models and clinical features of human prion diseases have shown unfolded PrP accumulation results in endoplasmic reticulum (ER) stress. While ER stress-mediated apoptosis is responsible for neuronal loss in prion diseases, ER stress also activates the unfolded protein response (UPR) in an effort to restore ER homeostasis. Of the UPR signaling pathways, the PERK-eIF2α pathway is implicated in the pathogenesis of prion diseases. The proteasome protein degradation system is also activated during the UPR. Increasing evidence indicates that proteasome and autophagy activities are affected in prion diseases. These findings suggest that ER stress/UPR contributes to the onset of prion diseases. Hence, strategies that target the ER are useful approaches in treating prion diseases. Additionally, immunotherapeutic approaches for prion diseases have been developed in recent decades. Single-chain fragment variable antibodies targeting the accumulation of PrP are also beneficial in the prevention of abnormal PrP propagation. This review discusses pathogenic mechanisms related to the ER and potential strategies for treating prion diseases.