Ludwig Institute for Cancer Research, 171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12317-22. doi: 10.1073/pnas.1007088107. Epub 2010 Jun 21.
Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuroprotective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1alpha independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathological stress.
诱导神经营养基因的表达对于维持大脑受到应激损伤后的神经元完整性至关重要。在这里，我们表明，NR4A 核孤儿受体在神经元受到兴奋毒性和氧化应激后被诱导，上调神经营养基因，并增加神经元存活。此外，我们表明，NR4A 蛋白在暴露于应激损伤的神经元中由 cAMP 反应元件结合蛋白 (CREB) 诱导，并且它们作为 CREB 诱导的神经元存活的介质发挥作用。在六种 NR4A 等位基因中有三个缺失突变的动物在接受海人酸治疗后表现出氧化损伤增加、神经营养基因诱导减弱以及海马易损性增加。我们还证明，NR4A 和转录共激活因子 PGC-1alpha 独立地调节不同的 CREB 依赖性神经营养基因程序。这些数据表明，NR4A 核孤儿受体是神经病理学应激后神经保护的重要介质。
