Original Article

Citation: Cell Death and Disease (2015) 6, e1672; doi:10.1038/cddis.2015.49
Published online 5 March 2015

Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity
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M Halliday1,8, H Radford1,8, Y Sekine2, J Moreno1, N Verity1, J le Quesne1,3, C A Ortori4, D A Barrett4, C Fromont5, P M Fischer5, H P Harding2, D Ron2,6 and G R Mallucci1,7

  1. 1Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, UK
  2. 2Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
  3. 3Department of Histopathology, University Hospitals of Leicester NHS Trust, Leicester, UK
  4. 4Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, UK
  5. 5Division of Medicinal Chemistry & Structural Biology, School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK
  6. 6The Wellcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
  7. 7Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK

Correspondence: G Mallucci, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 OHQ, UK. Tel: +44 (0)01223 762043 or +44 (0)1162 525550; Fax: +44 116 5550; E-mail: grm7@le.ac.uk or gm522@cam.ac.uk

8These authors contributed equally to this work.

Received 9 January 2015; Accepted 19 January 2015

Edited by G Melino

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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 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.

Abbreviations:

AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; eIF2α, eukaryotic initiation factor 2 alpha; eIF2α-P, phosphorylated eukaryotic initiation factor 2 alpha; ER, endoplasmic reticulum; GADD34, growth arrest and DNA damage protein 34; ISR, integrated stress response; ISRIB, integrated stress response inhibitor; PD, Parkinson’s disease; PERK, pancreatic ER kinase; PERK-P, phosphorylated pancreatic ER kinase; PrP, prion protein; PrPSc, protease-resistant prion protein; RML, Rocky Mountain Laboratory; UPR, unfolded protein response; w.p.i., weeks post inoculation