title: Identification of a molecular target of psychosine and its role in globoid cell formation.
abstract: Globoid cell leukodystrophy (GLD) is characterized histopathologically by apoptosis of oligodendrocytes, progressive demyelination, and the existence of large, multinuclear (globoid) cells derived from perivascular microglia. The glycosphingolipid, psychosine (d-galactosyl-beta-1,1' sphingosine), accumulates to micromolar levels in GLD patients who lack the degradative enzyme galactosyl ceramidase. Here we document that an orphan G protein-coupled receptor, T cell death-associated gene 8, is a specific psychosine receptor. Treatment of cultured cells expressing this receptor with psychosine or structurally related glycosphingolipids results in the formation of globoid, multinuclear cells. Our discovery of a molecular target for psychosine suggests a mechanism for the globoid cell histology characteristic of GLD, provides a tool with which to explore the disjunction of mitosis and cytokinesis in cell cultures, and provides a platform for developing a medicinal chemistry for psychosine.
authors: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors: D S
authors: DS
authors: Im
authors: C E
authors: CE
authors: Heise
authors: T
authors: T
authors: Nguyen
authors: B F
authors: BF
authors: O'Dowd
authors: K R
authors: KR
authors: Lynch
mesh_terms: D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology / Q000503:physiopathology; D050356:Lipid Metabolism; D018613:Microscopy, Confocal; D015394:Molecular Structure; D009836:Oligodendroglia / Q000502:physiology*; D011609:Psychosine / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C513334:GPR65 protein, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D011609:Psychosine; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D002118:Calcium