Although accumulating evidence suggests that microglia-mediated neuroinflammation may be crucial for the initiation and progression of Parkinson's disease (PD), and that the control of neuroinflammation may be a useful strategy for preventing the degeneration of nigrostriatal dopaminergic (DA) projections in the adult brain, it is still unclear what kinds of endogenous biomolecules initiate microglial activation, consequently resulting in neurodegeneration. Recently, we reported that the increase in the levels of prothrombin kringle-2 (pKr-2), which is a domain of prothrombin that is generated by active thrombin, can lead to disruption of the nigrostriatal DA projection. This disruption is mediated by neurotoxic inflammatory events via the induction of microglial Toll-like receptor 4 (TLR4) in vivo , thereby resulting in less neurotoxicity in TLR4-deficient mice. Moreover, inhibition of microglial activation following minocycline treatment, which has anti-inflammatory activity, protects DA neurons from pKr-2-induced neurotoxicity in the substantia nigra (SN) in vivo. We also found that the levels of pKr-2 and microglial TLR4 were significantly increased in the SN of PD patients compared to those of age-matched controls. These observations suggest that there may be a correlation between pKr-2 and microglial TLR4 in the initiation and progression of PD, and that inhibition of pKr-2-induced microglial activation may be protective against the degeneration of the nigrostriatal DA system in vivo. To describe the significance of pKr-2 overexpression, which may have a role in the pathogenesis of PD, we have reviewed the mechanisms of pKr-2-induced microglial activation, which results in neurodegeneration in the SN of the adult brain.

中文翻译：

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凝血酶原Kringle-2：帕金森氏症多巴胺能系统中的潜在炎性病原体。

尽管越来越多的证据表明，小胶质细胞介导的神经炎症可能对帕金森氏病（PD）的发生和发展至关重要，并且控制神经炎症可能是防止成人大脑黑质纹状体多巴胺能（DA）变性的有用策略尚不清楚哪种内源性生物分子会引发小胶质细胞活化，从而导致神经变性。最近，我们报道凝血酶原kringle-2（pKr-2）的水平增加，这是活性凝血酶产生的凝血酶原的一个结构域，可导致黑纹状体DA投射的破坏。这种破坏是通过在体内诱导小胶质Toll样受体4（TLR4）引起的神经毒性炎症事件介导的，从而导致TLR4缺陷小鼠神经毒性降低。此外，在具有抗炎活性的米诺环素治疗后，对小胶质细胞活化的抑制作用可保护DA神经元免受体内黑质（SN）中pKr-2诱导的神经毒性。我们还发现，与年龄匹配的对照组相比，PD患者的SN中pKr-2和小胶质TLR4的水平显着增加。这些观察表明，PD的起始和进展中pKr-2和小胶质细胞TLR4之间可能存在相关性，并且抑制pKr-2诱导的小胶质细胞活化可能对体内黑质纹状体DA系统的变性具有保护作用。为了描述pKr-2过表达的意义（可能在PD的发病机理中起作用），