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PERKing up neurons, sparing the pancreas
The unfolded protein response (UPR) is critical for proteostasis in all tissues. However, chronic UPR activity in protein aggregation–associated neurodegenerative diseases detrimentally suppresses protein synthesis that is necessary for neuronal function and survival, as well as for cognition. Hughes et al. found that the phosphorylation of a threonine residue in the stress response kinase PERK reduced its interaction with the translation initiation factor eIF2α but left PERK’s kinase activity intact. This partial inhibition approach reduced neuronal loss and increased survival in a mouse model of prion disease without the pancreatic damage seen with catalytic inhibitors of PERK. The findings suggest that therapeutics targeting eIF2α-interaction phosphosites may be a viable neuroprotective strategy.
Abstract
Chronic activation of the unfolded protein response (UPR), notably the branch comprising the kinase PERK and the translation initiation factor eIF2α, is a pathological feature of many neurodegenerative diseases caused by protein misfolding. Partial reduction of UPR signaling at the level of phosphorylated eIF2α is neuroprotective and avoids the pancreatic toxicity caused by full inhibition of PERK kinase activity. However, other stress pathways besides the UPR converge on phosphorylated eIF2α in the integrated stress response (ISR), which is critical to normal cellular function. We explored whether partial inhibition of PERK signaling may be a better therapeutic option. PERK-mediated phosphorylation of eIF2α requires its binding to the insert loop within PERK’s kinase domain, which is, itself, phosphorylated at multiple sites. We found that, as expected, Akt mediates the phosphorylation of Thr799 in PERK. This phosphorylation event reduced eIF2α binding to PERK and selectively attenuated downstream signaling independently of PERK activity and the broader ISR. Induction of Thr799 phosphorylation with a small-molecule activator of Akt similarly reduced PERK signaling and increased both neuronal and animal survival without measurable pancreatic toxicity in a mouse model of prion disease. Thus, promoting PERK phosphorylation at Thr799 to partially down-regulate PERK-eIF2α signaling while avoiding widespread ISR inhibition may be a safe therapeutic approach in neurodegenerative disease.
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