Identification of a molecular target of psychosine and its role in globoid cell formation.
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.
Im
D S
DS
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Heise
C E
CE
Nguyen
T
T
O'Dowd
B F
BF
Lynch
K R
KR
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
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