Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2 alpha kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2 alpha signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2 alpha signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2 alpha in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2 alpha phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as 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 alpha signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.

Automated summary

Proper regulation of PERK-eIF2 alpha signaling in midbrain dopamine neurons is essential for normal cognitive and motor function. Chronic activation of this pathway has been implicated in the pathophysiology of various neurological diseases.