RT Journal Article SR Electronic T1 Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice JF Science Translational Medicine FD American Association for the Advancement of Science SP 206ra138 OP 206ra138 DO 10.1126/scitranslmed.3006767 VO 5 IS 206 A1 Moreno, Julie A. A1 Halliday, Mark A1 Molloy, Colin A1 Radford, Helois A1 Verity, Nicholas A1 Axten, Jeffrey M. A1 Ortori, Catharine A. A1 Willis, Anne E. A1 Fischer, Peter M. A1 Barrett, David A. A1 Mallucci, Giovanna R. YR 2013 UL http://stm.sciencemag.org/content/5/206/206ra138.abstract AB During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.