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Journal of Lipid Research, Vol. 47, 1478-1492, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

S. Giri^*, M. Khan^*, R. Rattan, I. Singh^* and A. K. Singh^1,

^* Department of Pediatrics and Department of Pathology and Laboratory Medicine, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic/Foundation, Rochester, MN 55905
Department of Pathology and Laboratory Medicine, Ralph Johnson Veterans Affairs Medical Center, Charleston, SC 29425

Published, JLR Papers in Press, April 27, 2006.

¹ To whom correspondence should be addressed. e-mail: singhi{at}musc.edu

Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside ß-galactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose- and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.

Supplementary key words twitcher • apopoptosis • sPLA2 inhibitor • LPC

Abbreviations: AA, arachidonic acid; CAT, chloramphenicol acetyltransferase; CNS, central nervous system; cPLA₂, cytosolic phospholipase A₂; DCFDA, 6-carboxy 2', 7'-dichlorodihydrofluorescein diacetate; DEDA, 7,7-dimethyl eicosadienoic acid; iPLA₂, calcium-independent phospholipase A₂; LPC, lysophosphatidylcholine; NAC, N-acetylcysteine; PLA2, phospholipase A2; ROS, reactive oxygen species; sPLA2, secretory phospholipase A2; TNF, tumor necrosis factor-

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