title: Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3.
abstract: 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 microM 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.
authors.affiliation: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD 20892, USA. SchueleU@ninds.nih.gov
authors.forename: U H
authors.initials: UH
authors.lastname: Schueler
authors.forename: T
authors.initials: T
authors.lastname: Kolter
authors.forename: C R
authors.initials: CR
authors.lastname: Kaneski
authors.forename: J K
authors.initials: JK
authors.lastname: Blusztajn
authors.forename: M
authors.initials: M
authors.lastname: Herkenham
authors.forename: K
authors.initials: K
authors.lastname: Sandhoff
authors.forename: R O
authors.initials: RO
authors.lastname: Brady
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003470:Culture Media / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005776:Gaucher Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005962:Glucosylceramidase / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011609:Psychosine / Q000031:analogs & derivatives; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D003470:Culture Media; D011609:Psychosine; C035742:sphingosyl beta-glucoside; D013108:Sphingomyelin Phosphodiesterase; D001616:beta-Galactosidase; D005962:Glucosylceramidase; D000109:Acetylcholine; D013110:Sphingosine