Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci DR, Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013;5(206):206-138.

Over recent years, our knowledge of the pathophysiological mechanisms of neurodegeneration underlying prion diseases has greatly expanded; in particular related to the so-called “unfolded protein response” (UPR). The UPR has multiple pathways, including the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, which leads to inhibition of the translation of messenger RNA and decreased synthesis of multiple proteins, including synaptic proteins.[1] When unopposed, this mechanism induces synaptic failure and cell death.

In the article by Moreno et al,2 inhibiting the UPR downstream from the abnormal protein prevented neurodegeneration in prion-infected mice. Considering that the UPR is a universal reaction of the cell to abnormal misfolded proteins, such action will apply not only to prion scrapie proteins but also to α-synuclein, amyloid, and others. Thus this finding could change the way we approach neuroprotection for other neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Previous studies have demonstrated that modulation of the UPR via focal gene delivery is effective in animal models of prion diseases and Alzheimer's disease,1,3 yet an oral medication has the theoretical advantage of preventing neurodegeneration throughout the brain.

In this study, GSK2606414, an oral inhibitor of PERK, was given to prion-infected mice before (7 weeks after infection, n = 20) or after (9 weeks after infection, n = 9) clinical symptoms and neurodegeneration were established. None of the mice in the active-treatment groups (n = 29) developed clinical disease, whereas all the untreated animals had established clinical prion disease (n = 20). Compared to untreated mice, both treatment groups had improvements in terms of behavioral testing (as measured by burrowing activity), histopathological changes (neuronal counts, spongiform changes, and astrocytosis) and protein synthesis. However, late treatment did not reverse established memory loss (as measured by novel object exploratory preference).

Survival analysis could not be performed as the treated mice lost >20% of their weight and had to be killed according to UK ethical guidelines. The weight loss and increased levels of blood glucose were attributed to exocrine and endocrine pancreatic failure, which is known to be associated with PERK dysfunction.4 The systemic side effects will limit the widespread application of GSK2606414, and this issue needs to be resolved before such drugs can be used in humans.

Moreover, sustained inhibition of this adaptive stress response may have long-term negative impacts on normal cell function. Further studies will need to examine the impact on survival and the long-term effects of inhibition of the UPR, especially if this method is to be applied to other neurodegenerative diseases with a more protracted course. Studies in other disease models now need to be performed to confirm the applicability to synuclein, tau and amyloid protein. However, this study suggests a new target and strategy to prevent neurodegeneration in PD.

  • Isabelle Beaulieu-Boire, MD, FRCPC and Susan H. Fox, MBChB, MRCP (UK), PhD

  • Morton & Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, Toronto, Ontario, Canada


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  2. References
  • 1
    Moreno JA, Radford H, Peretti D, et al. Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Nature 2012;485:507-511.
  • 2
    Moreno JA, Halliday M, Molloy C, et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013;5:206ra138.
  • 3
    Ma T, Trinh MA, Wexler AJ, et al. Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat Neurosci 2013;16:1299-1305.
  • 4
    Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in Perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell 2001;7:1153-1163.