Bose Anindita, Mouton-Liger François, Paquet Claire, Mazot Pierre, Vigny Marc, Gray Françoise, Hugon Jacques
Inserm UMRS, Institut du Fer à Moulin, Paris, FranceDepartments of Histology Pathology The Memory Clinical Center, Lariboisière Hospital (APHP), University Paris Diderot VII, Paris, France.
Brain Pathol. 2011 Mar;21(2):189-200. doi: 10.1111/j.1750-3639.2010.00437.x. Epub 2010 Oct 3.
Double-stranded RNA dependent kinase (PKR) is a pro-apoptotic kinase that controls protein translation. Previous studies revealed that activated PKR is increased in brains with Alzheimer's disease (AD). Glycogen Synthase Kinase Aβ (GSK-3β) is responsible for tau phosphorylation and controls several cellular functions also including apoptosis. The goal of this work was to determine if PKR could concurrently trigger GSK-3β activation, tau phosphorylation and apoptosis. In AD brains, both activated kinases co-localize with phosphorylated tau in neurons. In SH-SY5Y cell cultures, tunicamycin and Aβ(1-42) activate PKR, GSK-3β and induce tau phosphorylation and all these processes are attenuated by PKR inhibitors or PKR siRNA. Our results demonstrate that neuronal PKR co-localizes with GSK-3β and tau in AD brains and is able to modulate GSK-3β activation, tau phosphorylation and apoptosis in neuroblastoma cells exposed to tunicamycin or Aβ. PKR could represent a crucial signaling point relaying stress signals to neuronal pathways leading to cellular degeneration in AD.
双链RNA依赖性激酶（PKR）是一种控制蛋白质翻译的促凋亡激酶。先前的研究表明，在患有阿尔茨海默病（AD）的大脑中，活化的PKR会增加。糖原合酶激酶Aβ（GSK-3β）负责tau蛋白磷酸化，并控制包括细胞凋亡在内的多种细胞功能。这项工作的目的是确定PKR是否能同时触发GSK-3β活化、tau蛋白磷酸化和细胞凋亡。在AD大脑中，两种活化的激酶在神经元中均与磷酸化的tau蛋白共定位。在SH-SY5Y细胞培养物中，衣霉素和Aβ(1-42)可激活PKR、GSK-3β并诱导tau蛋白磷酸化，而PKR抑制剂或PKR siRNA可减弱所有这些过程。我们的结果表明，在AD大脑中，神经元PKR与GSK-3β和tau蛋白共定位，并且能够调节暴露于衣霉素或Aβ的神经母细胞瘤细胞中的GSK-3β活化、tau蛋白磷酸化和细胞凋亡。PKR可能是一个关键的信号转导点，将应激信号传递至导致AD中细胞变性的神经元通路。
