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A more recent version of this article appeared on July 1, 2006

Papers In Press, published online ahead of print April 27, 2006
J. Lipid Res., doi:10.1194/jlr.M600084-JLR200
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Submitted on February 17, 2006
Revised on April 26, 2006
Accepted on April 27, 2006

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

Shailendra Giri, Mushfiquidin Khan, Ramandeep Rattan, Inderjit Singh, and Avtar K. Singh

Pediatrics, MUSC, Charleston, SC 29425

Corresponding Author: singhi{at}musc.edu

Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by pathognomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme (galactocerebroside -galactosidase). This study underscores the mechanism of action of psychosine in the regulation oligodendrocyte cell death via 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, thus indicating a PLA2-dependent pathobiology, in brains of Krabbe disease patient and twitcher mice, an animal model of Krabbe disease. In vitro studies of treatment of primary oligodendrocyte and oligodendrocyte MO3.13 cell line with psychosine also resulted in the generation of LPC and release of AA in a dose and time dependent manner thus indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic and secretory PLA2 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 secretory PLA2 (sPLA2). An inhibitor of sPLA2 (7,7-dimethyl eicosadienoic acid, DEDA) completely attenuated the psychosine mediated accumulation of LPC levels, release of AA and generation of ROS and blocked oligodendroyte cell death as evident from cell survival, DNA fragmentation and caspase 3 activity assays. This study for the first time documents that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection of oligodendrocyte cell death and resulting demyelination in Krabbe disease.


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