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J. Biol. Chem. 278 (32): 29496-29501

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibition of Calcium Uptake via the Sarco/Endoplasmic Reticulum Ca2+-ATPase in a Mouse Model of Sandhoff Disease and Prevention by Treatment with N-Butyldeoxynojirimycin*

Dori Pelled {ddagger} §, Emyr Lloyd-Evans {ddagger} § ¶, Christian Riebeling {ddagger} ||, Mylvaganam Jeyakumar ¶ **, Frances M. Platt ¶ {ddagger}{ddagger}, and Anthony H. Futerman {ddagger} §§

{ddagger}Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel and Department of Biochemistry, Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom

Abstract: 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.

Received for publication March 24, 2003. Revision received May 15, 2003.

* Hexb mice were obtained from the laboratory of Prof. Dr. Konrad Sandhoff and Dr. Gerhild van Echten-Deckert, University of Bonn, in the framework of a grant from the German-Israel Foundation for Scientific Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Contributed equally to this work.

|| Supported by a Research Training Network Fellowship HPRN-CT-2000-00077 from the European Union.

** Supported by The Wellcome Trust.

{ddagger}{ddagger} Lister Institute Research Fellow.

§§ To whom correspondence should be addressed. Tel.: 972-8-9342704; Fax: 972-8-9344112; E-mail: tony.futerman{at}

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