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PKR and PP1C Polymorphisms in Alzheimer’s Disease Risk

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Author(s): Ernest Palomer | Gerard ILL-Raga | Marta Tajes | Eva Ramos-Fernández | Mònica Bosch-Morató | Biuse Guivernau | José J. Galán | Jordi Clarimón | Carmen Antúnez | Mercé Boada | Luis M. Real | César Fandos | Francisco J. Muñoz

Journal: Neuroscience & Medicine
ISSN 2158-2912

Volume: 02;
Issue: 03;
Start page: 226;
Date: 2011;
Original page

Keywords: Alzheimer’s Disease | BACE1 | PKR | PP1 | eIF2α

ABSTRACT
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ß-peptide (Aß) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ß-site APP cleaving enzyme 1 (BACE1), a key enzyme in AD that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. Due to the functional relationship between BACE1, PKR, PP1 and AD we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with AD risk was found, our results show that neither rs7480390 nor rs2254958 are associated with AD susceptibility.
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