Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity.
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.
Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK.
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M
Halliday
Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK.
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H
Radford
Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
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Y
Sekine
Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK.
J
J
Moreno
Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK.
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Verity
1] Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK [2] Department of Histopathology, University Hospitals of Leicester NHS Trust, Leicester, UK.
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le Quesne
Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, UK.
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CA
Ortori
Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, UK.
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DA
Barrett
Division of Medicinal Chemistry & Structural Biology, School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
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C
Fromont
Division of Medicinal Chemistry & Structural Biology, School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
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Fischer
Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
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HP
Harding
1] Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK [2] The Wellcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
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Ron
1] Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK [2] Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
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Mallucci
D000081:Acetamides / Q000009:adverse effects / Q000627:therapeutic use*; D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002853:Chromatography, Liquid; D003514:Cyclohexylamines / Q000009:adverse effects / Q000627:therapeutic use*; D015151:Immunoblotting; D051379:Mice; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D053719:Tandem Mass Spectrometry
C000599093:2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide; D000081:Acetamides; D003514:Cyclohexylamines; D051701:Activating Transcription Factor 4