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Title: Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice
Authors: Moreno, Julie A.
Halliday, Mark
Molloy, Colin
Radford, Helois
Verity, Nicholas
Axten, Jeffrey M.
Ortori, Catharine A.
Willis, Anne E.
Fischer, Peter M.
Barrett, David A.
Mallucci, Giovanna R.
First Published: 9-Oct-2013
Publisher: American Association for the Advancement of Science
Citation: Science Translational Medicine, 2013, 5 (206), p. 206ra138
Abstract: During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.
DOI Link: 10.1126/scitranslmed.3006767
ISSN: 1946-6234
eISSN: 1946-6242
Type: Journal Article
Rights: Copyright © 2013, American Association for the Advancement of Science.
Description: Full text of this item is not currently available on the LRA. The final published version may be available through the links above.
Appears in Collections:Published Articles, Dept. of Cell Physiology and Pharmacology

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