Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice

@article{Moreno2013OralTT,
  title={Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice},
  author={Julie A Moreno and Mark Halliday and Colin Molloy and Helois Radford and Nicholas C. Verity and Jeffrey M. Axten and Catharine A. Ortori and Anne E. Willis and Peter M. Fischer and David A. Barrett and Giovanna R. Mallucci},
  journal={Science Translational Medicine},
  year={2013},
  volume={5},
  pages={206ra138 - 206ra138}
}
Pharmacological inhibition of PERK, the key kinase of the unfolded protein response that mediates translational shutdown, restores protein synthesis in prion-infected mice, thus preventing neurodegeneration and clinical disease. Perking Up Prion Disease Therapy There are no effective treatments for neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion disease. These diseases share common features, including the accumulation of misfolded disease… Expand
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TLDR
This study suggests a new target and strategy to prevent neurodegeneration in PD using GSK2606414, an oral inhibitor of PERK, and examines the impact on survival and the long-term effects of inhibition of the UPR. Expand
PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia
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The data support UPR-mediated translational failure as a generic pathogenic mechanism in protein-misfolding disorders, including tauopathies, that can be successfully targeted for prevention of neurodegeneration. Expand
Neurodegenerative disease: A PERK for the therapy of prion disease
TLDR
It is suggested that PERK could be targeted in neurodegenerative disorders that involve the UPR, and the orally available compound GSK2606414 also abolished established prion disease and restored the synthesis of synaptic proteins, although weight loss and hyperglycaemic side effects occurred. Expand
Targeting chaperones, heat shock factor-1, and unfolded protein response: Promising therapeutic approaches for neurodegenerative disorders
TLDR
The chaperones network and different approaches as the therapeutic targets for neurodegenerative diseases are described and the roles of molecular, chemical, and pharmacological chaperONES, as well as heat shock factor-1 and the unfolded protein response are discussed in detail. Expand
Unfolded Protein Response and Macroautophagy in Alzheimer’s, Parkinson’s and Prion Diseases
TLDR
While both the unfolded protein response and macroautophagy play an important role in the prevention and attenuation of AD and PD progression, only macroautrophagy seems to play anImportant role inThe development of PrDs. Expand
The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases
TLDR
All the aspects associated with targeted therapy against neurodegenerative proteopathies, including inhibition of the PERK-dependent UPR signaling branches are critically described. Expand
Translation dysregulation in neurodegenerative disorders
  • D. A. Bosco
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences
  • 2018
TLDR
Interestingly, these authors found that the effects of mutant FUS on translational repression extend to the nonsense-mediated decay (NMD) pathway, which reinforces the notion that translation dysregulation plays a role in neurodegenerative disease pathogenesis and highlight the factors involved in NMD as therapeutic targets for these disorders. Expand
Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model
TLDR
The results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway. Expand
Targeting of the unfolded protein response (UPR) as therapy for Parkinson's disease
TLDR
Most evidence linking ER stress to Parkinson's disease is overviewed, highlighting disturbances in the function of the endoplasmic reticulum (ER), the main subcellular compartment involved in protein folding and quality control. Expand
Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity
TLDR
Treatment with the small molecule ISRIB, which restores translation downstream of eIF2α, conferred neuroprotection in prion-diseased mice without adverse effects on the pancreas, and the data support the pursuit of this approach to develop new treatments for a range of neurodegenerative disorders that are currently incurable. Expand
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References

SHOWING 1-10 OF 35 REFERENCES
Sustained translational repression by eIF2α-P mediates prion neurodegeneration
TLDR
It is shown 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, and that promoting translational recovery in hippocampi of prionsinfected mice is neuroprotective. Expand
Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease
TLDR
Effective therapeutic knockdown of PrPC expression using RNAi in mice with established prion disease is shown and can be used to define the temporal, quantitative, and regional requirements for PrP knockdown for effective treatment of prions disease and to explore mechanisms involved in predegenerative neuronal dysfunction and its rescue. Expand
Perturbation of Endoplasmic Reticulum Homeostasis Facilitates Prion Replication*
TLDR
Analysis of PrP replication in vitro revealed that the PrP isoform generated after ER stress is more efficiently converted into PrPSc compared with the protein extracted from untreated cells, indicating that ER-damaged cells might be more susceptible to prion replication. Expand
The Disulfide Isomerase Grp58 Is a Protective Factor against Prion Neurotoxicity
TLDR
Investigation of the relationship between prion replication and induction of ER stress during different stages of the disease in a murine scrapie model indicates that expression of Grp58 is an early cellular response to prions replication, acting as a neuroprotective factor against prion neurotoxicity. Expand
RETRACTED: Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis
TLDR
This study shows that a full UPR, including induction of stress sensor kinases, chaperones and apoptotic mediators, is also present in spinal cords of human patients with sporadic disease and shows up-regulation of UPR prior to the onset of symptoms in SOD1 rodents, implying an active role in disease. Expand
Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice
TLDR
It is shown that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology and can be rescued, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). Expand
Activation of the unfolded protein response in Parkinson's disease.
TLDR
Data show that the UPR is activated in PD and that UPR activation is closely associated with the accumulation and aggregation of alpha-synuclein. Expand
The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus.
TLDR
Data indicate that UPR activation in AD neurons occurs at an early stage of neurofibrillary degeneration and suggest that the prolonged activation of the UPR is involved in both tau phosphorylation and neurodegeneration in AD pathogenesis. Expand
Expression of Mutant or Cytosolic PrP in Transgenic Mice and Cells Is Not Associated with Endoplasmic Reticulum Stress or Proteasome Dysfunction
TLDR
Results indicate that neither ER stress, nor perturbation of proteasome activity plays a major pathogenic role in prion diseases. Expand
Tau Accumulation Activates the Unfolded Protein Response by Impairing Endoplasmic Reticulum-Associated Degradation
TLDR
It is suggested that soluble tau impairs ERAD and the result is activation of the unfolded protein response (UPR), and the reversibility of this process suggests that tau-based therapeutics could significantly delay this type of cell death and therefore disease progression. Expand
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