PDF(Pubmed)
Abstract：
Parkinson\'s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and it is characterized by the intracellular and extracellular accumulation of α-synuclein (α-syn) and Tau, which are major components of cytosolic protein inclusions called Lewy bodies, in the brain. Currently, there is a lack of effective methods that preventing PD progression. It has been suggested that the plasminogen activation system, which is a major extracellular proteolysis system, is involved in PD pathogenesis. We investigated the functional roles of plasminogen in vitro in an okadaic acid-induced Tau hyperphosphorylation NSC34 cell model, ex vivo using brains from normal controls and methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, and in vivo in a widely used MPTP-induced PD mouse model and an α-syn overexpression mouse model. The in vitro, ex vivo and in vivo results showed that the administered plasminogen crossed the blood‒brain barrier (BBB), entered cells, and migrated to the nucleus, increased plasmin activity intracellularly, bound to α-syn through lysine binding sites, significantly promoted α-syn, Tau and TDP-43 clearance intracellularly and even intranuclearly in the brain, decreased dopaminergic neurodegeneration and increased the tyrosine hydroxylase levels in the substantia nigra and striatum, and improved motor function in PD mouse models. These findings indicate that plasminogen plays a wide range of pivotal protective roles in PD and therefore may be a promising drug candidate for PD treatment.
摘要：
帕金森病（PD）是第二大最常见的神经退行性疾病，它的特征是α-突触核蛋白（α-syn）和Tau的细胞内和细胞外积累，它们是细胞溶质蛋白质内含物的主要成分，称为路易体，在大脑中。目前,目前缺乏预防PD进展的有效方法.有人认为纤溶酶原激活系统，这是一个主要的细胞外蛋白水解系统，参与PD的发病机制。我们研究了纤溶酶原在冈田酸诱导的Tau过度磷酸化NSC34细胞模型中的体外功能作用，离体使用正常对照和甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的小鼠的大脑，以及在广泛使用的MPTP诱导的PD小鼠模型和α-syn过表达小鼠模型中的体内。在体外，离体和体内结果表明，施用的纤溶酶原穿过血脑屏障（BBB），进入细胞，迁移到细胞核，细胞内纤溶酶活性增加，通过赖氨酸结合位点与α-syn结合，显著促进α-syn，Tau和TDP-43清除细胞内，甚至在大脑中的核内清除，减少多巴胺能神经变性和增加酪氨酸羟化酶水平在黑质和纹状体,改善PD小鼠模型的运动功能。这些发现表明纤溶酶原在PD中起着广泛的关键保护作用，因此可能是PD治疗的有希望的药物候选物。
