HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 32, 29496-29501, August 8, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/32/29496    most recent M302964200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pelled, D. Articles by Futerman, A. H. Search for Related Content PubMed PubMed Citation Articles by Pelled, D. Articles by Futerman, A. H. Social Bookmarking                      What's this?

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  , Emyr Lloyd-Evans   ¶, Christian Riebeling  ||, Mylvaganam Jeyakumar ¶ **, Frances M. Platt ¶  and Anthony H. Futerman  

From the 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

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 V_max. 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 , and in revised form, 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.

Lister Institute Research Fellow.

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. E. Fox, X. Han, S. Kelly, A. H. Merrill Jr., R. E. Martin, R. E. Anderson, T. W. Gardner, and M. Kester Diabetes Alters Sphingolipid Metabolism in the Retina: A Potential Mechanism of Cell Death in Diabetic Retinopathy Diabetes, December 1, 2006; 55(12): 3573 - 3580. [Abstract] [Full Text] [PDF]

				A. Verkhratsky Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons Physiol Rev, January 1, 2005; 85(1): 201 - 279. [Abstract] [Full Text] [PDF]

				A. Cressant, N. Desmaris, L. Verot, T. Brejot, R. Froissart, M.-T. Vanier, I. Maire, and J. M. Heard Improved Behavior and Neuropathology in the Mouse Model of Sanfilippo Type IIIB Disease after Adeno-Associated Virus-Mediated Gene Transfer in the Striatum J. Neurosci., November 10, 2004; 24(45): 10229 - 10239. [Abstract] [Full Text] [PDF]

				D. t. Vruchte, E. Lloyd-Evans, R. J. Veldman, D. C. A. Neville, R. A. Dwek, F. M. Platt, W. J. van Blitterswijk, and D. J. Sillence Accumulation of Glycosphingolipids in Niemann-Pick C Disease Disrupts Endosomal Transport J. Biol. Chem., June 18, 2004; 279(25): 26167 - 26175. [Abstract] [Full Text] [PDF]

				C. Riebeling, J. C. Allegood, E. Wang, A. H. Merrill Jr., and A. H. Futerman Two Mammalian Longevity Assurance Gene (LAG1) Family Members, trh1 and trh4, Regulate Dihydroceramide Synthesis Using Different Fatty Acyl-CoA Donors J. Biol. Chem., October 31, 2003; 278(44): 43452 - 43459. [Abstract] [Full Text] [PDF]