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

Halliday, M.; Ortori, Catherine; Radford, H.; Barrett, Dave; Sekine, Y.; Fischer, Peter; Moreno, J.; Verity, N.; le Quesne, J.; Fromont, Christophe; Harding, H.P.; Ron, D.; Mallucci, G.R.

Authors

M. Halliday

Catherine Ortori

H. Radford

Dave Barrett

Y. Sekine

Peter Fischer

J. Moreno

N. Verity

J. le Quesne

Christophe Fromont

H.P. Harding

D. Ron

G.R. Mallucci



Abstract

© 2015 Macmillan Publishers Limited All rights reserved. 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 molecule ISRIB, which restores translation downstream of eIF2α, conferred neuroprotection in prion-diseased mice without adverse effects on the pancreas. Critically, ISRIB treatment resulted in only partial restoration of global translation rates, as compared with the complete restoration of protein synthesis seen with GSK2606414. ISRIB likely provides sufficient rates of protein synthesis for neuronal survival, while allowing some residual protective UPR function in secretory tissue. Thus, fine-tuning the extent of UPR inhibition and subsequent translational de-repression uncouples neuroprotective effects from pancreatic toxicity. The data support the pursuit of this approach to develop new treatments for a range of neurodegenerative disorders that are currently incurable.

Citation

Halliday, M., Ortori, C., Radford, H., Barrett, D., Sekine, Y., Fischer, P., …Mallucci, G. (2015). Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death and Disease, 6, https://doi.org/10.1038/cddis.2015.49

Journal Article Type Article
Acceptance Date Jan 19, 2015
Online Publication Date Mar 5, 2015
Publication Date Mar 5, 2015
Deposit Date Oct 26, 2017
Publicly Available Date Mar 29, 2024
Journal Cell Death and Disease
Electronic ISSN 2041-4889
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 6
Article Number e1672
DOI https://doi.org/10.1038/cddis.2015.49
Public URL http://www.nature.com/cddis/journal/v6/n3/full/cddis201549a.html?foxtrotcallback=true
Publisher URL https://www.nature.com/articles/cddis201549
PMID 00035372

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