Research ArticlePrion Disease

Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice

Science Translational Medicine  09 Oct 2013:
Vol. 5, Issue 206, pp. 206ra138
DOI: 10.1126/scitranslmed.3006767

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Perking Up Prion Disease Therapy

There are no effective treatments for neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion disease. These diseases share common features, including the accumulation of misfolded disease-specific proteins in the brain, leading to neuronal loss, which is ultimately fatal. In addition, the brains of patients with these neurodegenerative diseases show overactivation of a cellular defense pathway for dealing with misfolded proteins called the unfolded protein response (UPR). The UPR deals with the misfolded protein load in a number of ways including transiently switching off translation. Moreno et al. now report that the buildup of misfolded prion protein in mice with prion disease causes sustained overactivation of this pathway. This results in long-term translational inhibition, causing a critical decline in key proteins needed for neuronal survival. The authors used a newly described specific inhibitor of a key UPR kinase mediating translational shutdown to test if pharmacological inhibition would be neuroprotective. The compound prevented neurodegeneration and the emergence of clinical disease in prion-infected mice, whereas untreated animals all succumbed to disease. These data suggest that the UPR may represent a new therapeutic target for drug development to treat prion disease and possibly other neurodegenerative diseases as well.