Fine-tuning PERK signaling for neuroprotection
Journal of Neurochemistry
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Halliday, M., Hughes, D., & Mallucci, G. (2017). Fine-tuning PERK signaling for neuroprotection. Journal of Neurochemistry https://doi.org/10.1111/jnc.14112
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.
Alzheimer's disease, neurodegeneration, neuroprotection, therapeutics, unfolded protein response
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.
Alzheimer's Drug Discovery Foundation (20141103)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647479)
External DOI: https://doi.org/10.1111/jnc.14112
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266979
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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