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Published online 16 April 2001. doi:10.1083/jcb.153.2.429
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© The Rockefeller University Press, 0021-9525/2001//429 $5.00
The Journal of Cell Biology, Volume 153, Number 2, , 2001 429-434

Report

Identification of a Molecular Target of Psychosine and Its Role in Globoid Cell Formation



Dong-Soon Ima, Christopher E. Heisea, Tuan Nguyenb, Brian F. O'Dowdb, and Kevin R. Lyncha

a Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908
b Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Department of Pharmacology, Box 800735, University of Virginia School of Medicine, 1300 Jefferson Park Ave., Charlottesville, VA 22908-0735.(804) 982-3878(804) 924-2840

krl2z{at}virginia.edu

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-β-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.

Key Words: psychosine • G protein–coupled receptor • cytokinesis • leukodystrophy • sphingolipid

© 2001 The Rockefeller University Press

Abbreviations used in this paper:GFP, green fluorescent protein; GlcPSY, D-glucosyl-β-1,1' sphingosine; GLD, globoid cell leukodystrophy; OGR1, ovarian cancer G protein–coupled receptor; PSY, psychosine; PTX, pertussis toxin; SPC, sphingosylphosphorylcholine; TDAG8, T cell death–associated gene 8.


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