Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
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
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
Gangliosides are found at high levels in neuronal tissues wherethey play a
variety of important functions. In the gangliosidoses,gangliosides accumulate
because of defective activity of thelysosomal proteins responsible for their
degradation, usuallyresulting in a rapidly progressive neurodegenerative
disease.However, the molecular mechanism(s) leading from ganglioside
accumulation to neurodegeneration is not known. We now examinethe effect of
ganglioside GM2 accumulation in a mouse modelof Sandhoff disease (one of the
GM2 gangliosidoses), the Hexb/mouse. Microsomes from
Hexb/ mouse brain showeda significant reduction in the rate of
Ca2+-uptake via thesarco/endoplasmic reticulum
Ca2+-ATPase (SERCA), which wasprevented by feeding
Hexb/ mice with N-butyldeoxynojirimycin(NB-DNJ), an
inhibitor of glycolipid synthesis that reducesGM2 storage. Changes in SERCA
activity were not due to transcriptionalregulation 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 establishedby the enhanced sensitivity of neurons cultured from
embryonicHexb/ mice to cell death induced by thapsigargin,a
specific SERCA inhibitor, and by the enhanced sensitivityof
Hexb/ microsomes to calcium-induced calciumrelease. This study
suggests a mechanistic link among GM2 accumulation,reduced SERCA activity,
and neuronal cell death, which maybe of significance for delineating the
neuropathophysiologyof Sandhoff disease.
Received for publication March 24, 2003.
Revision received May 15, 2003.
* Hexb mice were obtained from the laboratory of Prof. Dr. KonradSandhoff
and Dr. Gerhild van Echten-Deckert, University ofBonn, in the framework of a
grant from the German-Israel Foundationfor Scientific Research. The costs of
publication of this articlewere defrayed in part by the payment of page
charges. Thisarticle must therefore be hereby marked
"advertisement" inaccordance with 18 U.S.C. Section 1734
solely to indicate thisfact.
Contributed equally to this work.
|| Supported by a Research Training Network Fellowship HPRN-CT-2000-00077from
the European Union.
** Supported by The Wellcome Trust.
Lister Institute Research Fellow.
To whom correspondence should be addressed. Tel.: 972-8-9342704; Fax:
The editors suggest the following Related Resources on Science sites: