A study on pathogenesis and therapy of the lysosomal storage disease using ON-OFF (inducible transgeneic expression) system

我们试图通过可诱导的转基因基因表达系统，利用进行性神经系统疾病的模型--Sandhoff病小鼠模型，探索溶酶体储存性疾病的发病机制和治疗方法。由于我们的动物研究设施中发生了病毒和细菌的感染，我们无法很好地建立这个系统。相反，我们恰好发现了在Sandhoff病的发生和发展中非常重要的自身免疫特征。Sandhoff小鼠迅速发展成一种神经节苷脂GM2和GA2储存的进行性神经系统疾病。目前的研究表明，该模型中的疾病状态与抗神经节苷脂自身抗体的出现有关。在Sandhoff病的晚期，小鼠血清中抗神经节苷脂自身抗体的升高和中枢神经系统神经元的免疫球蛋白沉积，这些小鼠的血清转移显示出免疫球蛋白与神经元的结合。为了确定这些自身抗体的作用，在Sandhoff小鼠中还破坏了Fc受体Gamma基因(FcRGamma)，因为它在免疫复合体介导的自身免疫性疾病中发挥关键作用。FcRGamma基因缺失后，患者的临床症状得到改善，寿命延长。桑德霍夫鼠和小鼠的凋亡细胞数也有所减少。然而，神经节苷脂的积累水平并没有改变。一例尸检的SD患者的大脑中也证实了免疫球蛋白的沉积。综上所述，这些发现表明，自身抗体的产生在Sandhoff病的神经病变的发病机制中发挥着重要作用，因此为新的治疗方法提供了一个靶点。

We attemted to find the pathogenesis and therapy of the lysosomal storage disease using Sandhoff disease mice model, a model of progressive neurologic disease, via inducible transgenic gene expression system. Because of the viral and bacterial infections occured in our animal research facility, we could not build the system well.Instead, we happen to find the autoimmune features, that is very important, in the pathogenesis and development of the Sandhoff diease.Sandhoff mice rapidly develop a progressive neurologic disease of ganglioside GM2 and GA2 storage. The present study reveals that the disease-states in this model are associated with the appearance of anti-ganglioside autoantibodies. Both elevation of serum anti-ganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the Sandhoff disease in mice and serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor gamma gene (FcRgamma) was additionally disrupted in Sandhoff mice, as it plays a key role in immune complex mediated autoimmune diseases. Clinical symptoms were improved and lifespans were extended in the FcRgamma deleted. Sandhoff mice and the number of apoptotic cells were also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied SD patient. Taken together, these findings suggest that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in Sandhoff disease and therefore provides a target for novel therapies.