TITLE:
PKR and PP1C Polymorphisms in Alzheimer’s Disease Risk
AUTHORS:
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
KEYWORDS:
Alzheimer’s Disease, BACE1, PKR, PP1, eIF2α
JOURNAL NAME:
Neuroscience and Medicine,
Vol.2 No.3,
September
28,
2011
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.