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.

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.

• Authors: Dori Pelled, Emyr Lloyd-Evans, Christian Riebeling, Mylvaganam Jeyakumar, Frances M Platt, Anthony H Futerman
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 32 Pg. 29496-501 (Aug 08 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12756243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Gangliosides
• Glycolipids
• 1-Deoxynojirimycin
• G(M2) Ganglioside
• Thapsigargin
• Adenosine Triphosphate
• miglustat
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium-Transporting ATPases
• Calcium

Topics

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