Morel Milena, Couturier Julien, Pontcharraud Raymond, Gil Roger, Fauconneau Bernard, Paccalin Marc, Page Guylène
Research Group on Brain Aging, GReViC EA 3808, University of Poitiers, 6 rue de la Milétrie BP 199, 86034 Poitiers Cedex, France.
Neurobiol Dis. 2009 Oct;36(1):151-61. doi: 10.1016/j.nbd.2009.07.004. Epub 2009 Jul 23.
The control of translation is disturbed in Alzheimer's disease (AD). This study analysed the crosslink between the up regulation of double-stranded RNA-dependent-protein kinase (PKR) and the down regulation of mammalian target of rapamycin (mTOR) signalling pathways via p53, the protein Regulated in the Development and DNA damage response 1 (Redd1) and the tuberous sclerosis complex (TSC2) factors in two beta-amyloid peptide (Abeta) neurotoxicity models. In SH-SY5Y cells, Abeta42 induced an increase of P(T451)-PKR and of the ratio p66/(p66+p53) in nuclei and a physical interaction between these proteins. Redd1 gene levels increased and P(T1462)-TSC2 decreased. These disturbances were earlier in rat primary neurons with nuclear co-localization of Redd1 and PKR. The PKR gene silencing in SH-SY5Y cells prevented these alterations. p53, Redd1 and TSC2 could represent the molecular links between PKR and mTOR in Abeta neurotoxicity. PKR could be a critical target in a therapeutic program of AD.
阿尔茨海默病（AD）中翻译控制受到干扰。本研究分析了在两种β-淀粉样肽（Aβ）神经毒性模型中，双链RNA依赖性蛋白激酶（PKR）上调与雷帕霉素哺乳动物靶标（mTOR）信号通路下调之间通过p53、发育和DNA损伤反应调节蛋白1（Redd1）以及结节性硬化复合物（TSC2）因子形成的交联。在SH-SY5Y细胞中，Aβ42诱导细胞核中P（T451）-PKR及p66/（p66 + p53）比值增加，且这些蛋白之间存在物理相互作用。Redd1基因水平升高，P（T1462）-TSC2降低。在大鼠原代神经元中，这些干扰出现得更早，且Redd1和PKR在细胞核中共定位。SH-SY5Y细胞中PKR基因沉默可防止这些改变。p53、Redd1和TSC2可能代表Aβ神经毒性中PKR和mTOR之间的分子联系。PKR可能是AD治疗方案中的关键靶点。
