PKR and PP1C Polymorphisms in Alzheimer’s Disease Risk

• 作者: Biuse Guivernau Carmen Antúnez César Fandos Ernest Palomer Eva Ramos-Fernández Francisco J. Mu?oz Gerard ILL-Raga Jordi Clarimón José J. Galán Luis M. Real Marta Tajes Mercé Boada Mònica Bosch-Morató
• 来源期刊: 神经系统科学与医药(英文)
• 学科: 医学
• 关键词: Alzheimer’s DISEASE BACE1 PKR PP1 EIF2Α
• 年，卷（期）: 2011,（3）
• 页码范围: 226-231
• 页数: 6页
• 分类号: R73

摘要

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) 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 ?-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.