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Sustained translational repression by eIF2?-P mediates prion neurodegeneration

Moreno, Julie A.; Radford, Helois; Peretti, Diego; Steinert, Joern R.; Verity, Nicholas; Martin, Maria Guerra; Halliday, Mark; Morgan, Jason; Dinsdale, David; Ortori, Catherine A.; Barrett, David A.; Tsaytler, Pavel; Bertolotti, Anne; Willis, Anne E.; Bushell, Martin; Mallucci, Giovanna R.

Authors

Julie A. Moreno

Helois Radford

Diego Peretti

Joern R. Steinert

Nicholas Verity

Maria Guerra Martin

Mark Halliday

Jason Morgan

David Dinsdale

Catherine A. Ortori

David A. Barrett

Pavel Tsaytler

Anne Bertolotti

Anne E. Willis

Martin Bushell

Giovanna R. Mallucci



Abstract

The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders. © 2012 Macmillan Publishers Limited. All rights reserved.

Journal Article Type Article
Online Publication Date May 6, 2012
Publication Date May 24, 2012
Deposit Date Apr 15, 2019
Journal Nature
Print ISSN 0028-0836
Electronic ISSN 1476-4687
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 485
Issue 7399
Pages 507-511
DOI https://doi.org/10.1038/nature11058
Keywords Multidisciplinary
Public URL https://nottingham-repository.worktribe.com/output/1799270
Publisher URL https://www.nature.com/articles/nature11058
Additional Information A Corrigendum to this article was published on 16 July 2014


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