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

点击翻译按钮获取中文摘要

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.