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J Biol Chem, Vol. 274, Issue 31, 21673-21678, July 30, 1999
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From the Departments of Gaucher disease is a glycosphingolipid storage
disease caused by defects in the activity of the lysosomal hydrolase,
glucocerebrosidase (GlcCerase), resulting in accumulation of
glucocerebroside (glucosylceramide, GlcCer) in lysosomes. The acute
neuronopathic type of the disease is characterized by severe loss of
neurons in the central nervous system, suggesting that a neurotoxic
agent might be responsible for cellular disruption and neuronal death.
We now demonstrate that upon incubation with a chemical inhibitor of
GlcCerase, conduritol-B-epoxide (CBE), cultured hippocampal neurons
accumulate GlcCer. Surprisingly, increased levels of tubular
endoplasmic reticulum elements, an increase in
[Ca2+]i response to
glutamate, and a large increase in
[Ca2+]i release from the
endoplasmic reticulum in response to caffeine were detected in these
cells. There was a direct relationship between these effects and
GlcCer accumulation since co-incubation with CBE and an inhibitor
of glycosphingolipid synthesis, fumonisin B1, completely
antagonized the effects of CBE. Similar effects on endoplasmic
reticulum morphology and [Ca2+]i
stores were observed upon incubation with a short-acyl chain,
nonhydrolyzable analogue of GlcCer,
C8-glucosylthioceramide. Finally, neurons with elevated
GlcCer levels were much more sensitive to the neurotoxic effects of
high concentrations of glutamate than control cells; moreover, this
enhanced toxicity was blocked by pre-incubation with ryanodine,
suggesting that [Ca2+]i release
from ryanodine-sensitive intracellular stores can induce neuronal cell
death, at least in neurons with elevated GlcCer levels. These results
may provide a molecular mechanism to explain neuronal dysfunction and
cell death in neuronopathic forms of Gaucher disease.
Neurobiology and
¶ Biological Chemistry, The Weizmann Institute of Science, Rehovot
76100, Israel and the Kekulé-Institut für Organische
Chemie und Biochemie, Universitat Bonn, Bonn 53121, Germany
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