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Putting the Downstream Breaks on Neurodegeneration? 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.
The accumulation of misfolded or unfolded proteins and the subsequent challenge this poses to the neuron is a theme that is common to most neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and the prion diseases. Failure to adequately deal with this challenge leads to synaptic dysfunction and, ultimately, cell death. Much focus has been directed toward the individual rogue proteins involved in the abovedescribed disease states without the discovery of a significant disease-altering treatment. What if it is the neuron’s response to this challenge that ultimately proves fatal? Could this response be targeted for potential intervention in neurodegenerative disease, regardless of the upstream aberrant protein that triggered the downstream response? Reduced protein synthesis to reduce protein load is one means by which the cell responds to this challenge. It is achieved by the inhibition of mRNA translation through stressresponse pathways, many of which intersect at the phosphorylation of eukaryotic initiation factor 2a (eIF2a). One of these stress response pathways is the unfolded protein response (UPR), and this is triggered by altered homeostasis in the endoplasmic reticulum (ER). One of the four kinases that can phosporylate eIF2a, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is also one of the core signaling factors of the UPR, which itself is activated by phosphorylation (PERK-P). Raised levels of PERK-P and eIF2a-P are found in the brains of patients with AD, amyotrophic lateral sclerosis, prion disease, and PD.1 Last year, Moreno and colleagues demonstrated that sustained PERK activation in a mouse model of prion disease2 resulted in reduced production of synaptic proteins preceding neurodegeneration. A drug that inhibits the dephosphorylation of eIF2a (salubrinal) augmented neurodegeneration. In their current study, Moreno et al. set out to prove their hypothesis that the administration of a PERK inhibitor would be neuroprotective in this murine prion model. GSK26064124 is a newly described, selective inhibitor of PERK3 that has good blood-brain barrier penetration after oral administration. The tg37 mice that were studied overexpress prion protein (PrP) by three-fold and, thus, succumb to prion disease more rapidly than wild-type mice. Infection of these mice with Rocky Mountain Laboratory (RML) prion strain typically results in disease within 12 weeks. This murine prion disease model runs a stereotyped course. Mice develop synapse loss at week 7, memory loss at week 8, reduced protein synthesis and burrowing activity at week 9, neuronal loss at week 10, and clinical disease/death at week 12. Mice were intracerebrally inoculated with RML prions at 4 weeks. One group (n 5 20) was treated from 7 weeks before memory and behavioral deficits occurred and clinical signs were evident. A second group (n 5 9) was treated from 9 weeks, when spongiform pathology was evident and behavioral changes had occurred. Control mice (n 5 9 and n 5 8) were used in both groups and were treated with vehicle alone at 7 weeks and 9 weeks. Twelve weeks after inoculation, all GSK2606414-treated animals in both groups were free of disease, whereas all controls were terminally ill. Treatment at 7 weeks prevented loss of object recognition memory. Treatment at 9 weeks did not reverse the deficits recorded in object recognition memory but did reverse burrowing deficits. All sick control mice and GSK2606414treated mice were culled at 12 weeks. Mildly raised glucose levels and weight loss of 20% of body mass were observed in
-----------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25744
treated mice. UK Home Office regulations dictate the culling of such mice once this body mass has been lost; therefore, survival analysis was not performed. CA1 pyramidal neuron counts in GSK2606414-treated mice were equivalent to the counts in nonprion-infected mouse brains. In vehicle-treated mice, neuronal counts had dropped to 30% of control values. Levels of PrP and scrapie PrP (PrPSc) did not differ between the two groups; therefore, neuroprotection was observed despite ongoing prion replication. PERK activation/inhibition occurs downstream of prion replication. The study by Moreno et al. illuminates a potential new target for the pharmaceutical treatment of neurodegenerative disease.4 They have demonstrated in a murine prion model that treatment with GSK2606414, a selective PERK inhibitor, halts neurodegeneration and reverses behavioral changes seen in the mice treated at a later stage. Moderately raised glucose levels that did not reach murine diabetic levels and weight loss point to systemic side effects that will need close monitoring in the anticipated larger human studies. PERK plays an important role in the pancreas and in glucose homeostasis. Furthermore, all three pathways of the UPR are active in human disease,5 and the potential long-term effects of unbalanced UPR signaling are unknown. Neuroprotection is evident in this model despite the continued accumulation of prion protein. It is unknown whether these mice would have eventually developed clinical disease at some future point because of this ongoing accumulation. Nevertheless, the demonstration of such neuroprotection in a mouse model of prion disease is a potential game changer for neurodegeneration research. Allan McCarthy, MB, MRCPI John McKinley, MB, MMedSc, MRCP (UK) , and Tim Lynch, MB, BSc, DCH, FRCPI, FRCP, ABPN 1 Department of Neurology at the Dublin Neurological Institute, Mater Misericordiae University Hospital, Dublin, Ireland
References 1.
Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rosemuller JM, Scheper W. Activation of the unfolded protein response in Parkinson’s disease. Biochem Biophys Res Commun 2007;354:707-711.
2.
Moreno JA, Radford H, Peretti D. Sustained translational repression by eIF2alpa-P mediates prion neurodegeneration. Nature 2012;485: 507-511.
3.
Axten J, Medina JR, Feng Y, et al. Discovery of 7-methly-5-(1-{[3(trifluoromethyl)phenyl}acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem 2012;55:7193-7207.
4.
Halliday M, Malluci G. Targeting the unfolded protein response in neurodegeneration: a new approach to therapy. Neuropharmacology 2014;76(pt A):169-174.
5.
Roussel BD, Kruppa AJ, Miranda E. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 2013;12:105-118.
TOPICS
Putting the Downstream Breaks on Neurodegeneration? 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.
The accumulation of misfolded or unfolded proteins and the subsequent challenge this poses to the neuron is a theme that is common to most neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and the prion diseases. Failure to adequately deal with this challenge leads to synaptic dysfunction and, ultimately, cell death. Much focus has been directed toward the individual rogue proteins involved in the abovedescribed disease states without the discovery of a significant disease-altering treatment. What if it is the neuron’s response to this challenge that ultimately proves fatal? Could this response be targeted for potential intervention in neurodegenerative disease, regardless of the upstream aberrant protein that triggered the downstream response? Reduced protein synthesis to reduce protein load is one means by which the cell responds to this challenge. It is achieved by the inhibition of mRNA translation through stressresponse pathways, many of which intersect at the phosphorylation of eukaryotic initiation factor 2a (eIF2a). One of these stress response pathways is the unfolded protein response (UPR), and this is triggered by altered homeostasis in the endoplasmic reticulum (ER). One of the four kinases that can phosporylate eIF2a, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is also one of the core signaling factors of the UPR, which itself is activated by phosphorylation (PERK-P). Raised levels of PERK-P and eIF2a-P are found in the brains of patients with AD, amyotrophic lateral sclerosis, prion disease, and PD.1 Last year, Moreno and colleagues demonstrated that sustained PERK activation in a mouse model of prion disease2 resulted in reduced production of synaptic proteins preceding neurodegeneration. A drug that inhibits the dephosphorylation of eIF2a (salubrinal) augmented neurodegeneration. In their current study, Moreno et al. set out to prove their hypothesis that the administration of a PERK inhibitor would be neuroprotective in this murine prion model. GSK26064124 is a newly described, selective inhibitor of PERK3 that has good blood-brain barrier penetration after oral administration. The tg37 mice that were studied overexpress prion protein (PrP) by three-fold and, thus, succumb to prion disease more rapidly than wild-type mice. Infection of these mice with Rocky Mountain Laboratory (RML) prion strain typically results in disease within 12 weeks. This murine prion disease model runs a stereotyped course. Mice develop synapse loss at week 7, memory loss at week 8, reduced protein synthesis and burrowing activity at week 9, neuronal loss at week 10, and clinical disease/death at week 12. Mice were intracerebrally inoculated with RML prions at 4 weeks. One group (n 5 20) was treated from 7 weeks before memory and behavioral deficits occurred and clinical signs were evident. A second group (n 5 9) was treated from 9 weeks, when spongiform pathology was evident and behavioral changes had occurred. Control mice (n 5 9 and n 5 8) were used in both groups and were treated with vehicle alone at 7 weeks and 9 weeks. Twelve weeks after inoculation, all GSK2606414-treated animals in both groups were free of disease, whereas all controls were terminally ill. Treatment at 7 weeks prevented loss of object recognition memory. Treatment at 9 weeks did not reverse the deficits recorded in object recognition memory but did reverse burrowing deficits. All sick control mice and GSK2606414treated mice were culled at 12 weeks. Mildly raised glucose levels and weight loss of 20% of body mass were observed in
-----------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25744
treated mice. UK Home Office regulations dictate the culling of such mice once this body mass has been lost; therefore, survival analysis was not performed. CA1 pyramidal neuron counts in GSK2606414-treated mice were equivalent to the counts in nonprion-infected mouse brains. In vehicle-treated mice, neuronal counts had dropped to 30% of control values. Levels of PrP and scrapie PrP (PrPSc) did not differ between the two groups; therefore, neuroprotection was observed despite ongoing prion replication. PERK activation/inhibition occurs downstream of prion replication. The study by Moreno et al. illuminates a potential new target for the pharmaceutical treatment of neurodegenerative disease.4 They have demonstrated in a murine prion model that treatment with GSK2606414, a selective PERK inhibitor, halts neurodegeneration and reverses behavioral changes seen in the mice treated at a later stage. Moderately raised glucose levels that did not reach murine diabetic levels and weight loss point to systemic side effects that will need close monitoring in the anticipated larger human studies. PERK plays an important role in the pancreas and in glucose homeostasis. Furthermore, all three pathways of the UPR are active in human disease,5 and the potential long-term effects of unbalanced UPR signaling are unknown. Neuroprotection is evident in this model despite the continued accumulation of prion protein. It is unknown whether these mice would have eventually developed clinical disease at some future point because of this ongoing accumulation. Nevertheless, the demonstration of such neuroprotection in a mouse model of prion disease is a potential game changer for neurodegeneration research. Allan McCarthy, MB, MRCPI John McKinley, MB, MMedSc, MRCP (UK) , and Tim Lynch, MB, BSc, DCH, FRCPI, FRCP, ABPN 1 Department of Neurology at the Dublin Neurological Institute, Mater Misericordiae University Hospital, Dublin, Ireland
References 1.
Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rosemuller JM, Scheper W. Activation of the unfolded protein response in Parkinson’s disease. Biochem Biophys Res Commun 2007;354:707-711.
2.
Moreno JA, Radford H, Peretti D. Sustained translational repression by eIF2alpa-P mediates prion neurodegeneration. Nature 2012;485: 507-511.
3.
Axten J, Medina JR, Feng Y, et al. Discovery of 7-methly-5-(1-{[3(trifluoromethyl)phenyl}acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem 2012;55:7193-7207.
4.
Halliday M, Malluci G. Targeting the unfolded protein response in neurodegeneration: a new approach to therapy. Neuropharmacology 2014;76(pt A):169-174.
5.
Roussel BD, Kruppa AJ, Miranda E. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 2013;12:105-118.
