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

本研究拟通过诱导型转基因表达系统，建立一种进行性神经系统疾病的Sandhoff病小鼠模型，探讨溶酶体贮积症的发病机制及治疗方法。由于病毒和细菌的感染，我们不能很好地建立该系统，但我们发现了自身免疫的特点，这是非常重要的发病机制和发展的Sandhoff病，Sandhoff小鼠迅速发展成神经节苷脂GM 2和GA 2储存的进行性神经疾病。本研究揭示了该模型中的疾病状态与抗神经节苷脂自身抗体的出现相关。在小鼠桑德霍夫病晚期，发现血清抗神经节苷脂自身抗体升高和IgG沉积到中枢神经系统神经元，并且这些小鼠的血清转移显示IgG与神经元结合。为了确定这些自身抗体的作用，在Sandhoff小鼠中另外破坏Fc受体γ基因（FcRgamma），因为它在免疫复合物介导的自身免疫性疾病中起关键作用。在FcR γ缺失的患者中，临床症状得到改善，寿命延长。Sandhoff小鼠的凋亡细胞数也减少。然而，神经节苷脂的积累水平没有改变。IgG沉积也证实了尸检的SD患者的大脑。总之，这些研究结果表明，自身抗体的产生在桑德霍夫病神经病变的发病机制中起着重要作用，因此提供了一个新的治疗目标。

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.