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.

Hedgehog Signaling Modulates Glial Proteostasis and Lifespan

“…An additional readout for proteostasis function is the measure of pEIF2a levels that is indicative of the presence of misfolded proteins. The unfolded protein response (UPR) in the endoplasmic reticulum (ER) activates a signaling cascade that elevates pEIF2a levels (Halliday et al, 2017). We tested this using the pEIF2a antibody that has been used to quantify pEIF2a in Drosophila (Edenharter et al, 2018).…”

“…Our study demonstrates that glial overexpression of Hsp40 or Hsp68 is able to rescue proteostasis defects present in the hh mutant glial cells, characterized by an elevated level of ubiquitin. Interestingly, hh mutant flies also exhibit increased levels of pEIF2a, indicative of activation of the unfolded proteins response (Halliday et al, 2017), which can be restored to wildtype levels through glial expression of Hsp68. Conversely, Hhoverexpressing flies display reduced levels of pEIF2a, suggesting that stimulating Hh signaling is protective against protein misfolding.…”

Type I interferons and endoplasmic reticulum stress in health and disease

“…Similarly, the IRE1 axis also stimulates NF-κB activity by enforcing proteasomal degradation of IκB (Duran-Aniotz et al, 2017;Rubio et al, 2011;Tam et al, 2012). PERK commands a slightly different pathway for this purpose, it enforces translational inhibition of IκB thereby freeing NF-κB for engaging its transcriptional program (Blais et al, 2006;Halliday et al, 2017;Pytel et al, 2016;Qiao et al, 2017;Tam et al, 2012). Lastly, although ATF6 axis has been shown to influence NF-κB activation yet, the exact mechanism underlying this cascade has not been established (Tam et al, 2018;Yamazaki et al, 2009).…”

Hedgehog Signalling Modulates Glial Proteostasis and Lifespan

“…An additional readout for proteostasis function is the measure of pEIF2a levels which is indicative of the presence of misfolded proteins. The unfolded protein response (UPR) in the Endoplasmic reticulum (ER) activates a signalling cascade which elevates pEIF2a levels (Halliday et al, 2017). We tested this using the pEIF2a antibody, which has been used to quantify pEIF2a in Drosophila (Edenharter et al, 2018).…”

“…Interestingly, hh mutant flies also exhibit increased levels of pEIF2a, indicative of activation of the unfolded proteins response (Halliday et al, 2017), which can be restored to wild type levels through glial expression of Hsp68. Conversely, Hh overexpressing flies display reduced levels of pEIF2a, suggesting that stimulating Hh signalling is protective against protein misfolding.…”