Genetic reduction of PERK-eIF2α signaling in dopaminergic neurons drives cognitive and age-dependent motor dysfunction

An array of phenotypes in animal models of neurodegenerative disease have been shown to be reversed by neuronal inhibition of PERK, an eIF2 kinase that modulates the unfolded protein response (UPR). This suggests that targeting PERK therapeutically could be beneficial for treatment of human disease. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and age-dependent motor phenotypes. Conditional expression of phospho-mutant eIF2 in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2 phosphorylation. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as age-dependent changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2 signaling in DA neurons is required for normal cognitive and motor function across lifespan, and also highlight the need for caution in the proposed use of sustained PERK inhibition in neurons as a therapeutic strategy in the treatment of neurodegenerative disorders.