PMID- 12756243
OWN - NLM
STAT- MEDLINE
DCOM- 20030924
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 32
DP  - 2003 Aug 8
TI  - 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.
PG  - 29496-501
AB  - 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.
FAU - Pelled, Dori
AU  - Pelled D
AD  - Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, 
      Israel.
FAU - Lloyd-Evans, Emyr
AU  - Lloyd-Evans E
FAU - Riebeling, Christian
AU  - Riebeling C
FAU - Jeyakumar, Mylvaganam
AU  - Jeyakumar M
FAU - Platt, Frances M
AU  - Platt FM
FAU - Futerman, Anthony H
AU  - Futerman AH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030519
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Gangliosides)
RN  - 0 (Glycolipids)
RN  - 19130-96-2 (1-Deoxynojirimycin)
RN  - 19600-01-2 (G(M2) Ganglioside)
RN  - 67526-95-8 (Thapsigargin)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - ADN3S497AZ (miglustat)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - 1-Deoxynojirimycin/analogs & derivatives/*pharmacology
MH  - Adenosine Triphosphate/pharmacology
MH  - Animals
MH  - Blotting, Western
MH  - Brain/metabolism
MH  - Calcium/metabolism/*pharmacokinetics/pharmacology
MH  - Calcium-Transporting ATPases/*metabolism
MH  - Cell Death
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Endoplasmic Reticulum/*metabolism
MH  - Enzyme Inhibitors/*pharmacology
MH  - G(M2) Ganglioside/metabolism
MH  - Gangliosides/metabolism
MH  - Genotype
MH  - Glycolipids/metabolism
MH  - Hippocampus/cytology
MH  - Kinetics
MH  - Lipid Metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Microsomes/metabolism
MH  - Neurons/cytology/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sandhoff Disease/*metabolism
MH  - Sarcoplasmic Reticulum/*metabolism
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases
MH  - Spectrophotometry
MH  - Thapsigargin/pharmacology
MH  - Time Factors
EDAT- 2003/05/21 05:00
MHDA- 2003/09/25 05:00
CRDT- 2003/05/21 05:00
PHST- 2003/05/21 05:00 [pubmed]
PHST- 2003/09/25 05:00 [medline]
PHST- 2003/05/21 05:00 [entrez]
AID - S0021-9258(20)84209-4 [pii]
AID - 10.1074/jbc.M302964200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Aug 8;278(32):29496-501. doi: 10.1074/jbc.M302964200. Epub 2003 
      May 19.