Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases

• The UPR adapts ER proteostasis through translational attenuation and transcriptional remodeling.
• Activating distinct arms of the UPR differentially influences ER proteostasis.
• Arm-selective UPR activation shows promise to ameliorate protein misfolding diseases.
• Small molecules can manipulate independent arms of the UPR to change the fate of misfolded proteins.

Protein homeostasis (or proteostasis) within the endoplasmic reticulum (ER) is regulated by the unfolded protein response (UPR). The UPR consists of three integrated signaling pathways activated by the accumulation of misfolded proteins within the ER lumen. Activation of the UPR alters ER proteostasis through translational attenuation of new protein synthesis and transcriptional remodeling of ER proteostasis pathways, providing a mechanism to adapt ER proteostasis in response to cellular stress. The capacity of the UPR to alter ER proteostasis suggests that exogenous manipulation of UPR signaling pathways offers therapeutic promise to alter the fate of pathologic proteins associated with human protein misfolding diseases. Here, we discuss the therapeutic potential of exogenous UPR activation to treat human disease and highlight specific small molecule approaches for regulating UPR signaling that could be beneficial to treat protein misfolding diseases.