Abstract |
Gaucher disease is an inherited metabolic disorder caused by defective activity of the lysosomal enzyme, glucocerebrosidase, resulting in accumulation of the lipids, glucosylceramide (GlcCer), and glucosylsphingosine ( GlcSph). Little is known about the mechanism leading from lipid accumulation to disease, particularly in the acute and subacute neuronopathic forms of Gaucher disease, types 2 and 3, respectively. Recent work from our laboratory has shown, in animal models, that GlcCer enhances agonist-induced calcium release from intracellular stores via the ryanodine receptor, which results in neuronal cell death. We now test whether calcium release is altered in human brain tissue obtained post-mortem from Gaucher disease patients. Agonist-induced calcium release via the ryanodine receptor was significantly enhanced (P < 0.05) in brain microsomes from the acute neuronopathic form of Gaucher disease (type 2) (43 +/- 6% of the calcium in microsomes) compared to the subacute (type 3) (27 +/- 3%) and the non-neuronopathic (type 1) (28 +/- 6%) forms, and controls (18 +/- 3%), and correlated with levels of GlcCer accumulation. These findings suggest that defective calcium homeostasis may be a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease, and may potentially offer new therapeutic approaches for disease management.
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Authors | Dori Pelled, Selena Trajkovic-Bodennec, Emyr Lloyd-Evans, Ellen Sidransky, Raphael Schiffmann, Anthony H Futerman |
Journal | Neurobiology of disease
(Neurobiol Dis)
Vol. 18
Issue 1
Pg. 83-8
(Feb 2005)
ISSN: 0969-9961 [Print] United States |
PMID | 15649698
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Calcium Channel Agonists
- Glucosylceramides
- Ryanodine Receptor Calcium Release Channel
- Calcium
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Topics |
- Acute Disease
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Brain
(metabolism, pathology, physiopathology)
- Brain Chemistry
- Calcium
(metabolism)
- Calcium Channel Agonists
(pharmacology)
- Calcium Signaling
(genetics)
- Child, Preschool
- Gaucher Disease
(metabolism, pathology, physiopathology)
- Glucosylceramides
(metabolism)
- Humans
- Infant
- Infant, Newborn
- Microsomes
(chemistry, metabolism)
- Middle Aged
- Ryanodine Receptor Calcium Release Channel
(genetics)
- Up-Regulation
(genetics)
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