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Fine-tuning PERK signaling for neuroprotection

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journal contribution
posted on 2019-09-24, 15:36 authored by Mark Halliday, Daniel Hughes, Giovanna R. Mallucci
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.

Funding

GRM is funded by the Medical Research Council (MRC 5TR50), by a combined award from the Alzheimer's Society & Alzheimer's Drug Discovery Foundation (RG78185), by ERC Consolidator award (UPR Neuro) and by the UK DRI. The authors declare no conflicts of interest.

History

Citation

Journal of Neurochemistry, 2017, 142 (6), pp. 812-826

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES

Version

  • VoR (Version of Record)

Published in

Journal of Neurochemistry

Publisher

Wiley, International Society for Neurochemistry

issn

0022-3042

Acceptance date

2017-06-16

Copyright date

2017

Available date

2019-09-24

Publisher version

https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.14112

Notes

Corrigendum Volume 149 Issue 5 Journal of Neurochemistry pages: 699-699 First Published online: May 29, 2019 https://onlinelibrary.wiley.com/doi/10.1111/jnc.14714 "This work was supported by European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement UPR Neuro, No. 647479). Disclosure GRM is funded by the Medical Research Council (MRC 5TR50), by a combined award from the Alzheimer's Society & Alzheimer's Drug Discovery Foundation (RG78185), by ERC Consolidator award (UPR Neuro) and by the UK DRI. The authors declare no conflicts of interest."

Language

en

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