Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases

Abstract

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.

Figure 1

Adapting the proteostasis capacity of ERAF and ERAD pathways can attenuate the aberrant ER protein folding, trafficking or degradation processes involved in human protein misfolding disease pathology. (a) Left, illustration showing the excessive ERAD for destabilized, mutant proteins involved in loss-of-function protein misfolding diseases. Premature ERAD reduces trafficking of these mutants to their downstream functional environments, resulting in pathology that stems from low protein activities in their native environments. Right, illustration showing that increasing ERAF activity could attenuate the premature degradation of destabilized mutant proteins and increase trafficking to their downstream functional environment, allowing for increased protein activity. (b) Left, illustration showing the efficient folding and trafficking of destabilized, mutant proteins involved in gain-of-toxicity protein misfolding diseases. Efficient trafficking leads to high extracellular concentrations that facilitate pathologic concentration-dependent aggregation. Right, illustration showing that increasing ERAD activity could attenuate the secretion of these destabilized mutant proteins, reducing extracellular concentrations and decreasing concentration-dependent aggregation.

Figure 2

Activation of the three UPR signaling arms differentially influences ER proteostasis capacity. Illustration of downstream consequences of PERK, IRE1, or ATF6 activation on ER proteostasis. PERK activation leads to a reduced protein folding load mediated through translational attenuation and an increase in global proteostasis capacity mediated by the ATF4-dependent induction of genes involved in general cellular proteostasis maintenance including cellular redox regulation, amino acid biosynthesis, and negative feedback regulation of translational attenuation (i.e. GADD34). IRE1 activation increases ERAD/ERAF activity and induces ER expansion through the downstream activation of XBP1s. Furthermore, IRE1 can potentially attenuate ER protein folding load through the degradation of ER-localized mRNA. ATF6 activation leads to the cleavage of the active ATF6^NT transcription factor that primarily induces genes involved in ERAF and ERAD pathways.

Figure 3

Small molecule modulation of PERK signaling can be mediated by targeting eIF2α phosphatase complexes. PERK activation increases eIF2α phosphorylation, which in turn attenuates translation and increases expression of stress-responsive transcription factors. This pathway is negatively regulated by a phosphatase complex between protein phosphatase 1 and the constitutively expressed regulatory subunit CreP (PP1–CreP) and/or a stress-induced regulatory subunit GADD34 (PP1–GADD34). Small molecules that target these complexes can modulate eIF2α-dependent signaling, effectively mimicking PERK activation. Salubrinal inhibits both the PP1–CreP and PP1–GADD34 phosphatase complexes, allowing for increased eIF2α phosphorylation in the absence of stress. Guanabenz selectively targets PP1–GADD34, providing a mechanism to prolong PERK-dependent eIF2α phosphorylation signaling activation in response to ER stress. Figure adapted from Wiseman et al. [39].