Inherited defects in the degradation of sphingolipids cause a group of severe disorders known as sphingolipid storage diseases. Examples include Tay-Sachs, Sandhoff, Niemann-Pick and Gaucher diseases. There are currently no effective treatments for the majority of these diseases. Our work has focused on understanding disease pathogenesis in order to develop new therapeutic approaches. In particular we have been investigating the functions of sphingolipids to learn their potential roles in the disease process. We are systematically disrupting glycosphingolipid synthesis genes in the mouse to learn the function of this class of sphingolipid. We have found that the near complete elimination of the glycosphingolipid synthesis pathway critically impaired development and differentiation. However, a partial elimination of glycosphingolipid structures resulted in a surprisingly mild phenotype. Based on these results, we have explored a new treatment paradigm -- substrate deprivation therapy -- by constructing a genetic model in mice. Sandhoff disease mice, which abnormally accumulate glycosphinglipids, were bred with mice that were partially blocked in their synthesis of glycosphinglipids. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated glycosphinglipids, had improved neurologic function and had a much longer life span. These results demonstrated the validity of substrate deprivation therapy as a potential treatment paradigm for sphingolipid storage diseases. A practical application of the approach has been developed utilizing N-butlydeoxynojirimycin , a glycosphingolipid synthesis inhibitor, as a drug treatment for the glycosphingolipid storage diseases. - Tay-Sachs, Gaucher, Fabry, Sandhoff, sphingolipidosis, gangliosidosis
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