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Activation of PKR causes amyloid beta-peptide accumulation via De-Repression of Bace1 expression

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dc.contributor.author Ill-Raga, Gerard, 1982-
dc.contributor.author Palomer, Ernest
dc.contributor.author Wozniak, Matthew A
dc.contributor.author Ramos Fernández, Eva, 1984-
dc.contributor.author Bosch Morató, Mònica, 1986-
dc.contributor.author Tajes Orduña, Marta
dc.contributor.author Guix Ràfols, Francesc Xavier
dc.contributor.author Galán, José J
dc.contributor.author Clarimón Echevarría, Jordi
dc.contributor.author Antúnez, Carmen
dc.contributor.author Real, Luis M
dc.contributor.author Boada, Mercè
dc.contributor.author Itzhaki, Ruth F
dc.contributor.author Fandos, César
dc.contributor.author Muñoz López, Francisco José, 1964-
dc.date.accessioned 2015-05-04T08:56:20Z
dc.date.available 2015-05-04T08:56:20Z
dc.date.issued 2011
dc.identifier.citation Ill-Raga G, Palomer E, Wozniak MA, Ramos-Fernández E, Bosch-Morató M, Tajes M et al. Activation of PKR causes amyloid beta-peptide accumulation via De-Repression of Bace1 expression. PLoS ONE. 2011; 6(6): e21456. DOI 10.1371/journal.pone.0021456
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10230/23512
dc.description.abstract BACE1 is a key enzyme involved in the production of amyloid ß-peptide (Aß) in Alzheimer's disease (AD) brains. Normally, its expression is constitutively inhibited due to the presence of the 5′untranslated region (5′UTR) in the BACE1 promoter. BACE1 expression is activated by phosphorylation of the eukaryotic initiation factor (eIF)2-alpha, which reverses the inhibitory effect exerted by BACE1 5′UTR. There are four kinases associated with different types of stress that could phosphorylate eIF2-alpha. Here we focus on the double-stranded (ds) RNA-activated protein kinase (PKR). PKR is activated during viral infection, including that of herpes simplex virus type 1 (HSV1), a virus suggested to be implicated in the development of AD, acting when present in brains of carriers of the type 4 allele of the apolipoprotein E gene. HSV1 is a dsDNA virus but it has genes on both strands of the genome, and from these genes complementary RNA molecules are transcribed. These could activate BACE1 expression by the PKR pathway. Here we demonstrate in HSV1-infected neuroblastoma cells, and in peripheral nervous tissue from HSV1-infected mice, that HSV1 activates PKR. Cloning BACE1 5′UTR upstream of a luciferase (luc) gene confirmed its inhibitory effect, which can be prevented by salubrinal, an inhibitor of the eIF2-alpha phosphatase PP1c. Treatment with the dsRNA analog poly (I:C) mimicked the stimulatory effect exerted by salubrinal over BACE1 translation in the 5′UTR-luc construct and increased Aß production in HEK-APPsw cells. Summarizing, our data suggest that PKR activated in brain by HSV1 could play an important role in the development of AD
dc.description.sponsorship Neocodex is a private research organization (more than 70 articles in indexes of international research journals in the last 8 years). Neocodex’s work on this project was design, implementation, analysis and interpretation of genetic studies of the PKR gene that is included in this manuscript. Neocodex also coordinates the construction of the DNA bank employed in this draft. The work was carried out with funds from this entity and a project funded by the Alzheimur Foundation. The other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This w ork was also supported by the Spanish Ministerio de Ciencia y Tecnología (FIS: PI07/0593; Red HERACLES RD06/0009/002)
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartof PLoS ONE. 2011; 6(6): e21456
dc.rights © 2011 ILL-Raga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
dc.subject.other Proteïna beta-amiloide
dc.subject.other Cultius cel·lulars
dc.title Activation of PKR causes amyloid beta-peptide accumulation via De-Repression of Bace1 expression
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0021456
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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