中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (2): 212-213.doi: 10.4103/1673-5374.177712

• 观点:神经损伤修复保护与再生 • 上一篇    下一篇

组织型纤溶酶原激活剂是突触囊泡循环的调节剂？

  

  • 收稿日期:2015-11-23 出版日期:2016-02-15 发布日期:2016-02-15
  • 基金资助:

    这项工作部分得到美国国立卫生院NS-079331和NS-091201支持。

Tissue-type plasminogen activator is a modulator of the synaptic vesicle cycle

Manuel Yepes   

  1. Department of Neurology & Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, Veterans Affairs Medical Center, Atlanta, GA, USA
  • Received:2015-11-23 Online:2016-02-15 Published:2016-02-15
  • Contact: Manuel Yepes, M.D., myepes@emory.edu.
  • Supported by:

    This work has been supported in part by National Institutes of Health Grants NS-079331(to MY) and NS-091201 (to MY).

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摘要：

组织型纤溶酶原激活剂（tPA）是一种丝氨酸蛋白酶，其可催化纤溶酶原转化为纤维蛋白溶酶。在它发现之后的很长一段时间内，人们认为tPA主要来源于内皮细胞，因此其主要作用是在血管系统中产生纤溶酶。然而，这一概念在四十年后受到挑战，当时一组研究人员在大脑中明确限定的区域内，即海马、杏仁核、丘脑和下丘脑中确定了tPA的催化水解。值得注意的是，随后的研究工作表明，神经元而不是内皮细胞是中枢神经系统中tPA的主要储存器，并且大脑中的tPA在不需要纤溶酶原作为底物的条件下就会具有许多功能。有趣的是，虽然大多数已经进行的对神经元tPA的研究是从海马培养或海马切片细胞中得到，但较少有研究报道tPA是否在大脑皮质神经元中具有功能。我们实验室的研究发现，大脑皮层的tPA主要表达在簇小清蛋白阳性神经元轴突中，并且膜去极化可诱导此处的tPA快速释放。为了进一步表明tPA的轴突表达，野生型脑皮质神经元共染色抗tPA会大量表达在突触前末梢的蛋白质之中。这些研究显示，大约三分之一的轴突tPA在轴突柄中被发现。值得注意的是，这一比例在所有被检测轴突中均保持恒定，这表明了tPA可从轴突柄易位进入突触前末梢机构调节的存在。总之，可获得的数据表明tPA作为调节器在突触功能中发挥核心作用。还需要进一步研究以了解这种影响是否需要突触前终端表面上的tPA受体。

Abstract:

Tissue-type plasminogen activator (tPA) is a serine proteinase that catalyzes the conversion of plasminogen (PLG) into plasmin (Pl). For a long time after its discovery it was thought that tPA's main source was the endothelial cell and that therefore its chief role was to generate plasmin in the vascular system. However, this concept was challenged four decades later when a group of investigators identified tPA-catalyzed proteolysis in well-defined areas of the brain, namely the hippocampus, the amygdala, the thalamus and the hypothalamus. Remarkably, subsequent work indicated that neurons but not endothelial cells are the main reservoir of tPA in the central nervous system, and that in the brain tPA has many functions that do not require PLG as a substrate. Interestingly, while most of the studies on neuronal tPA have been performed either with cells cultured from the hippocampus or with hippocampal slices, fewer have investigated whether tPA has a function in cerebral cortical neurons. Research from our laboratory has found that in the cerebral cortex tPA is expressed mainly in axons from clusters of parvalbumin-positive neurons, and that membrane depolarization induces the rapid release of this tPA. To further characterize the axonal expression of tPA, wild-type cerebral cortical neurons were co-stained with antibodies against tPA and bassoon, a protein abundantly expressed in the presynaptic terminal. These studies revealed that approximately one-third of all axonal tPA is found in the axonal bouton. Remarkably, this proportion remained constant throughout all examined axons, suggesting the presence of a mechanism that regulates the translocation of tPA from the axonal shaft into the presynaptic terminal. In summary, the available data indicate that tPA plays a central role as a regulator of synaptic function. According to this model, the release of tPA from cerebral cortical neurons has a neuromodulatory effect on presynaptic function by inducing the anatomical and biochemical changes in the synaptic release site required for the release of excitatory neurotransmitters. Further studies are needed to understand whether this effect requires a receptor for tPA on the surface of the presynaptic terminal.