Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain
Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain
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DOI：
10.1073/pnas.1516729112
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发表时间：
2015-12-01
影响因子：
11.1
通讯作者：
Brann, Darrell
中科院分区：
文献类型：
--
作者：
Sareddy, Gangadhara R.;Zhang, Quanguang;Brann, Darrell
17-β雌二醇(E_2)在多种神经退行性疾病中具有神经保护作用。然而，其潜在的机制仍不清楚。在这里，我们使用前脑特异的基因敲除(FBKO)小鼠提供了遗传学证据，即雌激素受体共调节蛋白--富含脯氨酸、谷氨酸和亮氨酸的蛋白1(PELP1)在全脑缺血(GCI)后对E2在海马CA1区的核外信号和神经保护作用中起着至关重要的作用。在PELP1 FBKO小鼠GCI后，E2介导的核外信号转导(包括细胞外信号调节激酶和Akt的激活)和抗凋亡作用[如JNK信号转导减弱和糖原合成酶3β(GSK3β)磷酸化增加]受到影响。机制研究表明，PELP1与GSK3β相互作用，E2调节PELP1与GSK3β的相互作用，PELP1是GSK3β的新底物。对对照组和缺血后PELP1 FBKO小鼠的RNA-SEQ分析表明，PELP1 FBKO小鼠中与炎症、代谢和生存相关的几个基因发生了变化，Wnt/β-catenin信号通路的激活显著减少。此外，PELP1 FBKO研究表明，PELP1对于E2介导的神经保护和E2介导的GCI后认知功能的保护是必需的。总而言之，我们的数据提供了第一个直接的活体证据，据我们所知，PELP1在E2介导的快速核外信号传递、神经保护和大脑认知功能中发挥重要作用。
17-beta estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [ such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3 beta (GSK3 beta)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3 beta, E2 modulates interaction of PELP1 with GSK3 beta, and PELP1 is a novel substrate for GSK3 beta. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/beta-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.