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 diseases1,2,3,4, 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 dephosphorylation5, 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.
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Acknowledgements
We thank D. Read for imaging analysis, J. Edwards, T. Smith, J. McWilliam, P. Glynn, C. Molloy and University of Leicester, Department of Biological Services staff for technical assistance, J. Collinge (MRC Prion Unit) for the original RML prion inoculum, and K. Liddle for reading the manuscript. This work was funded by the Medical Research Council, UK.
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J.A.M. did most of the experimental work and analysis. N.V. and M.G.M. performed stereotaxic surgery and prion inoculations. H.R., D.P., M.H. and J.M. performed various experiments, D.D. performed electron microscopy, J.R.S. performed electrophysiological analysis, C.A.O. and D.A.B. performed mass spectrometry analysis, P.T. and A.B. worked with J.A.M. in Cambridge, A.E.W. and M.B. contributed expertise and direction on translational control mechanisms, and G.R.M. directed and supervised the project. J.A.M. and G.R.M. wrote the paper. All authors contributed to discussion, analysis of data and the final draft of paper.
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Moreno, J., Radford, H., Peretti, D. et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485, 507–511 (2012). https://doi.org/10.1038/nature11058
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DOI: https://doi.org/10.1038/nature11058
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