Journal
NEUROBIOLOGY OF DISEASE
Volume 14, Issue 3, Pages 595-601Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2003.08.016
Keywords
neuronopathic Gaucher disease; glucosylsphingosine; glucopsychosine; acetylcholine; cholinergic LA-N-2 cells
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Funding
- NATIONAL INSTITUTE OF MENTAL HEALTH [Z01MH001090, ZIAMH001090] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [Z01NS002982, R01NS042793] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG009525] Funding Source: NIH RePORTER
- NIA NIH HHS [AG09525] Funding Source: Medline
- NINDS NIH HHS [NS042793] Funding Source: Medline
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Patients with Gaucher disease have been classified as type 1 nonneuronopathic, type 2 acute neuronopathic, and type 3 chronic neuronopathic phenotypes. Increased quantities of glucocerebroside and glucosylsphingosine (glucopsychosine) are present in the brain of type 2 and type 3 Gaucher patients. Galactosylsphingosine has previously been shown to be neurotoxic in globoid cell leukodystrophy (Krabbe disease). To determine whether glucosylsphingosine is also neurotoxic, we examined its effect on cultured cholinergic neuron-like LA-N-2 cells. When these cells were exposed to 1, 5, or 10 muM glucosylsphingosine for a period of 18 h, they became shriveled, neurite outgrowth was suppressed, and the activities of the lysosomal enzymes glucocerebrosidase, sphingomyelinase, and beta-galactosidase were reduced in a dose-dependent manner. Acetylcholine in cells exposed to glucosylsphingosine also declined. Cells switched to glucosylsphingosine-free medium partially recovered. The data suggest that accumulation of glucosylsphingosine contributes to neuronal dysfunction and destruction in patients with neuronopathic Gaucher disease. (C) 2003 Elsevier Inc. All rights reserved.
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