Establishment of the amyotrophic lateral sclerosis therapy by midkine

由于肌萎缩侧索硬化症(ALS)是一种病因不明的顽固性神经退行性疾病，迫切需要建立有效的新的治疗方法。因此，在本研究中，我们建立了神经生长因子之一的中期因子(MK)治疗ALS的新方法。为了建立中期因子治疗ALS的新方法，我们首次制备了两种类型的MK抗体：一种是仅识别人MK的单抗，另一种是识别人、小鼠和大鼠MK的多克隆抗体。其次，我们分析了两个家系的40例散发性ALS和5例家族性ALS，以及3个ALS动物模型系：G1H-G93A小鼠、G93A大鼠和H46R大鼠。不仅在人类尸检病例中，而且在ALS动物模型中，一些运动神经元表达MK以维持再次ALS应激。第三，我们培育了MK过表达转基因小鼠(MK-TG)，它在运动神经元中强烈表达MK。第四，我们成功地建立了突变的SOD1-MK高表达双转基因(MK-ALS TG)小鼠。临床上，MK-ALS转基因小鼠的存活时间明显长于ALS转基因小鼠。在MK-ALS TG小鼠中，与不表达MK的运动神经元相比，MK-组织病理学高表达的运动神经元存活时间更长。本研究结果表明，MK对ALS引起的运动神经元死亡具有保护作用，并为MK治疗ALS提供了新的途径。

Since amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease with unknown etiology, the effective new therapy establishment is strongly desired. In this study, therefore, we have established the new ALS therapy by midkine (MK), which is one of nerve growth factors.For the establishment of the new ALS therapy by midkine, for the first time, we have produced two types of MK antibodies: one is a monoclonal antibody which recognizes only human MK and the other is a polyclonal antibody which recognizes MK among human, mouse, and rat. Second, we have analyzed 40 cases of human sporadic ALS and 5 cases of familial ALS with mutant SOD1 of two families, in addition to 3 lines of ALS animal models: G1 H-G93A mice, G93A rats, and H46R rats. In not only human autopsy cases but also ALS animal models, some motor neurons express MK in order to survive again ALS stress. Third we have produced MK overexpressing transgenic (MK-Tg) mice, which strongly express MK in motor neurons. Fourth, we have succeeded in producing mutation SOD1-MK overexpressing double transgenic (MK-ALS Tg) mice. MK-ALS Tg mice have shown a longer survival in comparison with ALS Tg mice clinically. In MK-ALS Tg mice, MK-histopathologically-overexpressing motor neurons have longer survived, compared with motor neurons without expression MK.This study results that MK protects motor neuron death caused by ALS, and provides a new ALS therapy by MK.