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Gangliosides are found at high levels in neuronal tissues where they play a variety of important functions. In the gangliosidoses, gangliosides accumulate because of defective activity of the lysosomal proteins responsible for their degradation, usually resulting in a rapidly progressive neurodegenerative disease. However, the molecular mechanism(s) leading from ganglioside accumulation to neurodegeneration is not known. We now examine the effect of ganglioside GM2 accumulation in a mouse model of Sandhoff disease (one of the GM2 gangliosidoses), the Hexb-/- mouse. Microsomes from Hexb-/- mouse brain showed a significant reduction in the rate of Ca2+-uptake via the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), which was prevented by feeding Hexb-/- mice with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glycolipid synthesis that reduces GM2 storage. Changes in SERCA activity were not due to transcriptional regulation but rather because of a decrease in Vmax. Moreover, exogenously added GM2 had a similar effect on SERCA activity. The functional significance of these findings was established by the enhanced sensitivity of neurons cultured from embryonic Hexb-/- mice to cell death induced by thapsigargin, a specific SERCA inhibitor, and by the enhanced sensitivity of Hexb-/- microsomes to calcium-induced calcium release. This study suggests a mechanistic link among GM2 accumulation, reduced SERCA activity, and neuronal cell death, which may be of significance for delineating the neuropathophysiology of Sandhoff disease.

Original publication




Journal article


J Biol Chem

Publication Date





29496 - 29501


1-Deoxynojirimycin, Adenosine Triphosphate, Animals, Blotting, Western, Brain, Calcium, Calcium-Transporting ATPases, Cell Death, Disease Models, Animal, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Endoplasmic Reticulum, Enzyme Inhibitors, G(M2) Ganglioside, Gangliosides, Genotype, Glycolipids, Hippocampus, Kinetics, Lipid Metabolism, Mice, Mice, Transgenic, Microsomes, Neurons, Reverse Transcriptase Polymerase Chain Reaction, Sandhoff Disease, Sarcoplasmic Reticulum, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Spectrophotometry, Thapsigargin, Time Factors