Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity

Cell Death & Disease
Mark HallidayGiovanna R Mallucci

Abstract

Activation of the PERK branch of the unfolded protein response (UPR) in response to protein misfolding within the endoplasmic reticulum (ER) results in the transient repression of protein synthesis, mediated by the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α). This is part of a wider integrated physiological response to maintain proteostasis in the face of ER stress, the dysregulation of which is increasingly associated with a wide range of diseases, particularly neurodegenerative disorders. In prion-diseased mice, persistently high levels of eIF2α cause sustained translational repression leading to catastrophic reduction of critical proteins, resulting in synaptic failure and neuronal loss. We previously showed that restoration of global protein synthesis using the PERK inhibitor GSK2606414 was profoundly neuroprotective, preventing clinical disease in prion-infected mice. However, this occured at the cost of toxicity to secretory tissue, where UPR activation is essential to healthy functioning. Here we show that pharmacological modulation of eIF2α-P-mediated translational inhibition can be achieved to produce neuroprotection without pancreatic toxicity. We found that treatment with the small ...Continue Reading

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Citations

Jul 15, 2015·Expert Opinion on Therapeutic Targets·Alexis RivasClaudio Hetz
Dec 3, 2015·Proceedings of the National Academy of Sciences of the United States of America·Qiujing YuSerge Y Fuchs
Mar 30, 2016·Brain Research·Oliver J Freeman, Giovanna R Mallucci
Oct 10, 2015·Acta Neuropathologica·Helois RadfordGiovanna R Mallucci
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