From the Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, and.
J Biol Chem. 2018 Jun 15;293(24):9234-9247. doi: 10.1074/jbc.RA118.002534. Epub 2018 May 2.
Synaptic repair in the ischemic brain is a complex process that requires reorganization of the actin cytoskeleton. Ezrin, radixin, and moesin (ERM) are a group of evolutionarily conserved proteins that link the plasma membrane to the actin cytoskeleton and act as scaffolds for signaling transduction. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface and activates intracellular signaling pathways. Early studies indicate that uPA and uPAR expression increase during the recovery phase from an ischemic stroke and that uPA binding to uPAR promotes neurorepair in the ischemic brain. The and studies presented here show that either the release of neuronal uPA or treatment with recombinant uPA induces the local synthesis of ezrin in the synapse and the recruitment of β3-integrin to the postsynaptic density (PSD) of cerebral cortical neurons by a plasminogen-independent mechanism. We found that β3-integrin has a double effect on ezrin, inducing its recruitment to the PSD via the intercellular adhesion molecule-5 (ICAM-5) and its subsequent activation by phosphorylation at Thr-567. Finally, our data indicate that by triggering the reorganization of the actin cytoskeleton in the postsynaptic terminal, active ezrin induces the recovery of dendritic spines and synapses that have been damaged by an acute ischemic stroke. In summary, our data show that uPA-uPAR binding promotes synaptic repair in the ischemic brain via ezrin-mediated reorganization of the actin cytoskeleton in the postsynaptic terminal.
缺血性脑内的突触修复是一个复杂的过程，需要肌动蛋白细胞骨架的重组。埃兹蛋白（Ezrin）、根蛋白（Radixin）和膜突蛋白（Moesin）（ERM）是一组进化上保守的蛋白质，它们将质膜与肌动蛋白细胞骨架连接起来，并作为信号转导的支架。尿激酶型纤溶酶原激活物（uPA）是一种丝氨酸蛋白酶，与尿激酶型纤溶酶原激活物受体（uPAR）结合后，在细胞表面催化纤溶酶原转化为纤溶酶，并激活细胞内信号通路。早期研究表明，uPA 和 uPAR 的表达在缺血性中风的恢复阶段增加，而 uPA 与 uPAR 的结合促进缺血性脑内的神经修复。本文提出的研究表明，神经元 uPA 的释放或重组 uPA 的治疗以纤溶酶原非依赖性机制诱导突触内 ezrin 的局部合成和 β3-整合素向大脑皮质神经元突触后密度（PSD）的募集。我们发现，β3-整合素有双重作用于 ezrin，通过细胞间黏附分子-5（ICAM-5）诱导其募集到 PSD，并通过 Thr-567 的磷酸化使其随后被激活。最后，我们的数据表明，通过触发突触后末端肌动蛋白细胞骨架的重组，活性 ezrin 诱导因急性缺血性中风而受损的树突棘和突触的恢复。总之，我们的数据表明，uPA-uPAR 结合通过 ezrin 介导的突触后末端肌动蛋白细胞骨架的重组促进缺血性脑内的突触修复。
