Abstract
Krabbe disease is a fatal rare inherited lipid storage disorder affecting 1:100,000 births. This illness is caused by mutations in the galc gene encoding for the enzyme galactosylceramidase (GALC). Dysfunction of GALC has been linked to the toxic build-up of the galactolipid, galactosylsphingosine (psychosine), which induces cell death of oligodendrocytes. Previous studies show that phospholipase A2 (PLA2) may play a role in psychosine induce cell death. Here, we demonstrate that non-selective inhibition of cPLA2/sPLA2 and selective inhibition of cPLA2, but not sPLA2, also attenuates psychosine-induced cell death of human astrocytes. This study shows that extracellular calcium is required for psychosine induced cell death, but intracellular calcium release, reactive oxygen species or release of soluble factors are not involved. These findings suggest a cell autonomous effect, at least in human astrocytes. Supporting a role for PLA2 in psychosine-induced cell death of oligodendrocytes and astrocytes, the results show inhibition of PLA2 attenuates psychosine-induced decrease in the expression of astrocyte marker vimentin as well as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and the neuronal marker SMI-32 in organotypic slice cultures. These findings provide further mechanistic details of psychosine-induced death of glia and suggest a role for PLA2 in the process. This work also supports the proposal that novel drugs for Krabbe disease may require testing on astrocytes as well as oligodendrocytes for more holistic prediction of pre-clinical and clinical efficacy.
Highlights
Krabbe disease is a rare inherited lipid storage disorder resulting in oligodendrocyte cell death and subsequent loss of myelin
Having shown previously that psychosine causes astrocyte toxicity that can be attenuated by sphingosine 1-phosphate receptor (S1PR) drugs [17, 18], here we aimed to examine further the pathways involved in psychosine-induced astrocyte cell death and in this study focussed on the role of phospholipase A2 (PLA2) in this process
Given that PLA2 plays a role in psychosine toxicity of human oligodendrocytes cell lines [9], we examined if the same held true for astrocytes
Summary
Krabbe disease is a rare inherited lipid storage disorder resulting in oligodendrocyte cell death and subsequent loss of myelin. Krabbe disease is associated with mutations in the galc gene encoding for the enzyme galactosylceramidase (GALC) [1] resulting in the build-up of one particular galactolipid, called psychosine, which is suspected to be responsible for the pathology of this illness [2]. Most studies on Krabbe disease have focused on the toxicity of psychosine on oligodendrocytes. Several pathways have been associated with psychosine-induced.
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