Figure 7
From: A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models
Model of the effects of mutant Htt and the action of MK-28. Accumulation of misfolded mHtt inhibits ERAD, causing ER stress and inducing the activation of the UPR to either reestablish cellular homeostasis or trigger cell death. In the activation of the PERK pathway of the UPR, unfolded ER proteins bind to the chaperone BiP, allowing oligomerization and autophosphorylation of PERK, which phosphorylates eIF2α. EIF2α-P causes a transient global suppression of protein translation, reducing the ER protein load and ER stress. EIF2α-P also promotes the translation of ATF4, upregulating beneficial UPR target genes required for autophagy, antioxidant response, and amino acid metabolism. MK-28 activates PERK, extending the beneficial transient inhibition of protein synthesis and alleviating the ER load, promoting cell survival. This strategy does not affect the activation of GADD34, which promotes the restoration of translation in the long term by reduction of eIF2α-P. This, together with the reduction in ER stress prevents initiation of apoptosis.
