Fine-tuning PERK signaling for neuroprotection

Abstract

Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress because of protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch, is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the tauopathies. Recently, numerous genetic and pharmacological studies in mice have demonstrated the effectiveness of inhibiting the UPR for eliciting therapeutic benefit and boosting memory. In particular, fine-tuning the level of PERK inhibition to provide neuroprotection without adverse side effects has emerged as a safe, effective approach. This includes the recent discovery of licensed drugs that can now be repurposed in clinical trials for new human treatments for dementia. This review provides an overview of the links between UPR overactivation and neurodegeneration in protein misfolding disorders. It discusses recent therapeutic approaches targeting this pathway, with a focus on treatments that fine-tune PERK signaling.

Keywords: Alzheimer's disease; neurodegeneration; neuroprotection; therapeutics; unfolded protein response.

Figure 1

The unfolded protein response. The presence of misfolded proteins causes the dissociation of BiP from the three unfolded protein response (UPR) sensors, protein kinase RNA (PKR) like ER kinase (PERK), IRE1 and activating transcription factor 6 (ATF6), leading to their activation. PERK phosphorylates eIF2α, leading to translational repression and the up‐regulation of a subset of UPR target genes including activating transcription factor 4 (ATF4) and the pro‐apoptotic CHOP. PERK also phosphorylates nuclear factor (erythroid‐derived)‐like 2 (Nrf2), leading to its dissociation from the inhibitory Keap1. Nrf2 is then free to activate genes with an ARE involved with the redox/antioxidant response. IRE1 activation leads to the splicing of X‐box binding protein 1 spliced (XBP1), which then activates many UPR target genes related to protein folding, lipid synthesis, protein translocation into the ER and ER‐associated decay (ERAD). ATF6 activation targets genes under the control of an ER stress response element (ERSE), including molecular chaperones (such as BiP), folding enzymes and components of the ERAD system.

Figure 2

The unfolded protein response (UPR) and ISR converge on eIF2α phosphorylation, leading to a reduction in ternary complex. Protein kinase RNA (PKR) like ER kinase (PERK), PKR, GCN2 and HRI all phosphorylate eIF2α in response to a variety of stresses. Under normal conditions, the three subunits of eIF2 form ternary complex with methionine transfer RNA and GTP supplied by the guanine exchange factor eIF2B. This complex is then loaded into the ribosome with the mRNA to be translated, forming the pre‐initiation complex. When eIF2α is phosphorylated, it binds tightly to eIF2B, preventing it from exchanging GDP to GTP. This prevents the formation of ternary complex and potently inhibits the initiation of translation.

Figure 3

Modulating the unfolded protein response (UPR) to prevent neurodegeneration. Disease associated misfolded proteins activate protein kinase RNA (PKR) like ER kinase (PERK) signaling across the spectrum of neurodegenerative disease. Chronic translational repression is associated with neurodegeneration in several experimental model and human tissue samples. Genetic ablation of PERK, PKR and GCN2 improves learning and memory and neurodegenerative phenotypes, along with over‐expression of the eIF2α phosphatase GADD34. Small molecule inhibitors of PERK (GSK2606414), or compounds that promote ternary complex formation (ISRIB, trazodone and DBM) also restore translation and prevent neurodegeneration. Inhibitors of GADD34, such as salubrinal, guanabenz and sephin1 have been reported to enhance or protect against neurodegeneration depending on the experimental model used.

Figure 4

Repurposed drugs prevent neurodegeneration in models of prion and frontotemporal dementia (FTD). Two compounds, trazodone and DBM, recently uncovered in a screen for unfolded protein response (UPR) inhibitors prevent neurodegeneration in the prion and FTD mouse models of disease. Both compounds are effective when administered after synaptic dysfunction has begun. Trazodone also reduced phosphorylated tau aggregation in the FTD model. The compounds act downstream of eIF2α‐P to increase ternary complex levels. Adapted from (Halliday et al. 2017).