Double stranded RNA activated EIF2 α kinase (EIF2AK2; PKR) is associated with Alzheimer's disease

Bullido, María J.; Martínez-García, Ana; Tenorio, Raquel; Sastre, Isabel; Muñoz, David G.; Frank, Ana; Valdivieso, Fernando

doi:10.1016/j.neurobiolaging.2007.02.023

« Previous Next »Neurobiology of Aging
Volume 29, Issue 8 , Pages 1160-1166, August 2008

Double stranded RNA activated EIF2 α kinase (EIF2AK2; PKR) is associated with Alzheimer's disease

María J. Bullido
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Ana Martínez-García
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
- These two authors contributed equally to this work.
Raquel Tenorio
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
- These two authors contributed equally to this work.
Isabel Sastre
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
David G. Muñoz
- University of Toronto & St. Michael's Hospital, Toronto, Canada
Ana Frank
- Servicio de Neurología, Hospital Universitario La Paz (UAM), 28034 Madrid, Spain
Fernando Valdivieso
- Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
- Corresponding author. Tel.: +34 91 497 84 71; fax: +34 91 497 48 70.

Received 26 October 2006; received in revised form 9 February 2007; accepted 15 February 2007. published online 11 April 2007.

Abstract

Sporadic Alzheimer's disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors (for example virus infections). To test this hypothesis, we are examining human genes relevant to herpes simplex virus type 1 (HSV-1) infection via genetic association studies in AD case–control samples. Recently, we found that a variant in TAP2, a major target used by HSV-1 to evade immune surveillance, is associated with AD. The present work analyses another gene involved in the host cell response to HSV-1, EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2; coding for PKR); PKR mediates the virus-induced shut-off of translation, and levels of activated PKR are high in the brains of AD patients. An EIF2AK2 SNP (rs2254958) located in the 5′-UTR region within an exonic splicing enhancer was found to be associated with AD. More specifically: the C allele was more commonly found in the patients and, compared to non-CC genotypes, the CC homozygotes showed earlier (around 3.3 years) onset of AD, especially in the absence of the APOE4 allele. These results further support the hypothesis that variants of human genes participating in HSV-1 infection modulate the susceptibility and/or clinical manifestations of AD.

Keywords: Alzheimer, Genetic association, PKR, EIF2AK2, Onset age