During prion disease, an increase in misfolded prion protein leads to sustained overactivation of an unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, synaptic failure and neuronal death. 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.
In the current study, Moreno and colleagues show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase), prevented UPR-mediated translational repression and hindered development of clinical prion disease in mice, with neuroprotection observed throughout the brain. This was the case for mice treated both at the preclinical stage and also later in the disease when behavioral signs had emerged. The authors 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.
Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR: Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice. Science Transl. Med. 5: 206ra138 (2013).