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Papers In Press, published online ahead of print May 19, 2003
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100
Corresponding Author: tony.futerman{at}weizmann.ac.il
Gangliosides are found at high levels in neuronal tissues where they play a variety of important functions. In the gangliosidoses, gangliosides accumulate due to 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 to 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 between GM2 accumulation, reduced SERCA activity, and neuronal cell death, which may be of significance for delineating the neuropathophysiology of Sandhoff disease.
J. Biol. Chem, 10.1074/jbc.M302964200
Submitted on March 24, 2003
Revised on May 15, 2003
Accepted on May 19, 2003
Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) in a mouse model of Sandhoff disease, and prevention by treatment with N-butyldeoxynojirimycin
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