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Glycosphingolipid - cholesterol abnormalities in NPC2 - deficient neurons appear equivalent to those occurring in neurons lacking NPC1, suggesting NPC1 - NPC2 molecular cooperation



Glycosphingolipid - cholesterol abnormalities in NPC2 - deficient neurons appear equivalent to those occurring in neurons lacking NPC1, suggesting NPC1 - NPC2 molecular cooperation



Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 537 15



Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by accumulation of glycosphingolipids (GSLs) and cholesterol and by profound CNS dysfunction. Approximately 5% of NPC patients harbor defects in NPC2, also known as HE1, a soluble lysosomal protein of unknown function, while the rest possess defects in NPC1, an integral membrane protein with homology to Patched and HMG CoA reductase. NPC2 protein is known to bind cholesterol and NPC1 believed associated with retroendocytic trafficking of cholesterol, consistent with the primacy of cholesterol storage in NPC disease. However, recent studies in which NPC1-/-mice were crossed with mice genetically deficient in certain gangliosides (Gondre-Lewis and Walkley, 2003) revealed that cholesterol storage in NPC1-deficient neurons is ganglioside-dependent, suggesting more direct involvement of GSLs in NPC disease. We have initiated analysis of intraneuronal storage and other CNS disease features in mice lacking NPC2 and find remarkable similarity to NPC1-/-mice, including intraneuronal accumulation of free cholesterol and GM2 and GM3 gangliosides, meganeurite formation, neuroaxonal dystrophy and neuron death (Purkinje cell loss). By confocal analysis NPC2-/-and NPC1-/-mice showed similar patterns of ganglioside storage, including sequestration of GM2 and GM3 in separate vesicle populations suggesting independent mechanisms leading to their altered expression. The similarity of NPC2 and NPC1 diseases is consistent with molecular cooperation between the two proteins and raises the possibility that NPC2, like NPC1, is closely allied to homeostatic regulatory mechanisms controlling GSL homeostasis.

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