Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin

Mice deficient for plasminogen exhibit a variety of pathologies, all of which examined to date are reversed when the animals are also made fibrin(ogen) deficient. These results suggested that the predominant, and perhaps exclusive, physiological role of plasminogen is clearance of fibrin. Plasminogen-deficient mice also display resistance to excitotoxin-induced neurodegeneration, in contrast with wild-type mice, which are sensitive. Based on the genetic interaction between plasminogen and fibrinogen, we investigated whether resistance to neuronal cell death in the plasminogen-deficient mice is dependent on fibrin(ogen). Unexpectedly, mice lacking both plasminogen and fibrinogen are resistant to neurodegeneration to levels comparable to plasminogen-deficient mice. Therefore, plasmin acts on substrates other than fibrin during experimental neuronal degeneration, and may function similarly in other pathological settings in the central nervous system.

纤溶酶原（plasminogen）缺陷小鼠会表现出多种病理特征，而目前所有经检测的此类病理，在同时存在纤维蛋白（原）（fibrin(ogen)）缺陷的小鼠中均可得到逆转。上述结果提示，纤溶酶原主要且或许是唯一的生理学功能为清除纤维蛋白。与对兴奋性毒素诱导的神经退行性变敏感的野生型小鼠相比，纤溶酶原缺陷小鼠可表现出对该病变的抵抗性。基于纤溶酶原与纤维蛋白原之间的遗传互作，我们探究了纤溶酶原缺陷小鼠的神经元细胞死亡抵抗性是否依赖于纤维蛋白（原）。出乎意料的是，同时缺失纤溶酶原与纤维蛋白（原）的小鼠，其神经退行性变抵抗水平与仅缺失纤溶酶原的小鼠相当。因此，在实验性神经元退行性变过程中，纤溶酶可作用于纤维蛋白以外的底物，且在中枢神经系统的其他病理环境中可能发挥类似功能。