期刊
NEUROSCIENCE
卷 169, 期 4, 页码 1831-1839出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2010.06.016
关键词
eukaryotic initiation factor-2 alpha; Alzheimer's disease; double-stranded RNA-dependent protein kinase; PKR-like endoplasmic reticulum kinase; amino acids-regulated elF2 alpha kinase
资金
- Korean government A [R13-2008-023-01001]
- Asan Institute for Life Sciences, Seoul, Korea [08-067]
Phosphorylation of eukaryotic initiation factor-2 alpha (eIF2 alpha) is increased in Alzheimer's disease (AD) and this protein can be phosphorylated by several kinases, including double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), amino acids-regulated eIF2 alpha kinase (GCN2) and heme-regulated eIF2 alpha kinase (HRI). PKR and PERK especially are activated in the AD brain, and GCN2 is reported to increase presenilin-1 (PS1) activity. Okadaic acid (OA), a protein phosphatase-2A (PP2A) inhibitor, is known to increase tau phosphorylation, beta-amyloid (A beta) deposition and neuronal death, which are the pathological characteristics of AD. Here, we show that the phosphorylation of eIF2 alpha is increased and its kinases, PKR, PERK and GCN2 are activated in rat neurons by OA. Activating transcription factor (ATF4) which induces apoptosis in response to eIF2 alpha phosphorylation was increased and translocated to nuclei in OA-treated neurons. These results suggest that the successive events of activation of eIF2 alpha kinases and eIF2 alpha phosphorylation leading to ATF4 nuclear translocation may contribute to neuronal death. However, PKR inhibitors did not reduce eIF2 alpha phosphorylation or neuronal toxicity despite inhibiting PKR activity. These results suggest that PKR might not be the most responsible kinase for eIF2 alpha phosphorylation or cell death in PP2A-inhibited conditions such as AD. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据