Phospholipase A2 is involved in galactosylsphingosine-induced astrocyte toxicity, neuronal damage and demyelination

PLoS One. 2017 Nov 2;12(11):e0187217. doi: 10.1371/journal.pone.0187217. eCollection 2017.

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.

MeSH terms

  • Animals
  • Astrocytes / physiology*
  • Cells, Cultured
  • Demyelinating Diseases*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Neurons / pathology*
  • Phospholipases A2 / drug effects
  • Phospholipases A2 / physiology*
  • Psychosine / physiology*

Substances

  • Enzyme Inhibitors
  • Psychosine
  • Phospholipases A2

Grant support

This work was supported by the Trinity College Dublin, Irish Research Council; GOIPG/2015/2804 (http://research.ie/) and the Health Research Board; KEDS-2015-1614 and HRA-POR-2014-646 (http://www.hrb.ie/home/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.