Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3

U.H Schueler; T Kolter; C.R Kaneski; J.K Blusztajn; M Herkenham; K Sandhoff; R.O Brady

Neurobiology of Disease (Dec 2003)

Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3

U.H Schueler,
T Kolter,
C.R Kaneski,
J.K Blusztajn,
M Herkenham,
K Sandhoff,
R.O Brady

Affiliations

U.H Schueler: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD, USA; Kekulé-Institut für Organische Chemi und Biochemie der Universität, Bonn, Germany; Section on Functional Neuroanatomy, Laboratory of Cellular and Molecular Regulation, NIMH, NIH, DHHS, Bethesda, MD, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
T Kolter: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD, USA; Kekulé-Institut für Organische Chemi und Biochemie der Universität, Bonn, Germany; Section on Functional Neuroanatomy, Laboratory of Cellular and Molecular Regulation, NIMH, NIH, DHHS, Bethesda, MD, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
C.R Kaneski: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD, USA; Kekulé-Institut für Organische Chemi und Biochemie der Universität, Bonn, Germany; Section on Functional Neuroanatomy, Laboratory of Cellular and Molecular Regulation, NIMH, NIH, DHHS, Bethesda, MD, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
J.K Blusztajn: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD, USA; Kekulé-Institut für Organische Chemi und Biochemie der Universität, Bonn, Germany; Section on Functional Neuroanatomy, Laboratory of Cellular and Molecular Regulation, NIMH, NIH, DHHS, Bethesda, MD, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
M Herkenham: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD, USA; Kekulé-Institut für Organische Chemi und Biochemie der Universität, Bonn, Germany; Section on Functional Neuroanatomy, Laboratory of Cellular and Molecular Regulation, NIMH, NIH, DHHS, Bethesda, MD, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
K Sandhoff: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD, USA; Kekulé-Institut für Organische Chemi und Biochemie der Universität, Bonn, Germany; Section on Functional Neuroanatomy, Laboratory of Cellular and Molecular Regulation, NIMH, NIH, DHHS, Bethesda, MD, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
R.O Brady: Developmental and Metabolic Neurology Branch, NINDS, NIH, DHHS, Bethesda, MD, USA; Kekulé-Institut für Organische Chemi und Biochemie der Universität, Bonn, Germany; Section on Functional Neuroanatomy, Laboratory of Cellular and Molecular Regulation, NIMH, NIH, DHHS, Bethesda, MD, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA

Journal volume & issue: Vol. 14, no. 3
pp. 595 – 601

Abstract

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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 μM glucosylsphingosine for a period of 18 h, they became shriveled, neurite outgrowth was suppressed, and the activities of the lysosomal enzymes glucocerebrosidase, sphingomyelinase, and β-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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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