title: Role of endogenous psychosine accumulation in oligodendrocyte differentiation and survival: implication for Krabbe disease.
abstract: Krabbe disease is a lethal, demyelinating condition caused by genetic deficiency of galactocerebrosidase (GALC) and resultant accumulation of its cytotoxic substrate, psychosine (galactosylsphingosine), primarily in oligodendrocytes (OLs). Psychosine is generated by galactosylation of sphingosine by UDP-galactose:ceramide galactosyltransferase (CGT), a galactosylceramide synthesizing enzyme which is primarily expressed in OLs. The expression of CGT and the synthesis of galactosyl-sphingolipids are associated with the terminal differentiation of OL, but little is known about the participation of endogenous psychosine accumulation in OL differentiation under GALC deficient conditions. In this study, we report that accumulation of endogenous psychosine under GALC deficient Krabbe conditions impedes OL differentiation process both by decreasing the expression of myelin lipids and protein and by inducing the cell death of maturating OLs. The psychosine pathology under GALC deficient conditions involves participation of secretory phospholipase A2 (sPLA2) activation and increase in its metabolites, as evidenced by attenuation of psychosine-induced pathology by treatment with pharmacological inhibitor of sPLA2 7,7-dimethyleicosadienoic acid (DEDA). These observations suggest for potential therapeutic efficacy of sPLA2 inhibitor in Krabbe disease.
authors: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States.
authors: Je-Seong
authors: JS
authors: Won
authors: Jinsu
authors: J
authors: Kim
authors: Manjeet Kaur
authors: MK
authors: Paintlia
authors: Inderjit
authors: I
authors: Singh
authors: Avtar K
authors: AK
authors: Singh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005698:Galactosylceramidase / Q000378:metabolism; D005699:Galactosylceramides / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007965:Leukodystrophy, Globoid Cell / Q000378:metabolism* / Q000473:pathology*; D050356:Lipid Metabolism / Q000502:physiology; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D011609:Psychosine / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: D005699:Galactosylceramides; D011609:Psychosine; D005698:Galactosylceramidase