Globoid cell leukodystrophy (GLD) is a neurological disease caused by deficiency of the lysosomal
enzyme galactosylceramidase (GALC). In the absence of GALC, the cytotoxic
glycosphingolipid,
psychosine (psy), accumulates in the nervous system.
Psychosine accumulation preferentially affects oligodendrocytes, leading to progressive
demyelination and infiltration of activated monocytes/macrophages into the CNS. GLD is characterized by motor defects, cognitive deficits,
seizures, and death by 2-5 years of age. It has been hypothesized that
psychosine accumulation, primarily within
lipid rafts, results in the pathogenic cascade in GLD. However, the mechanism of
psychosine toxicity has yet to be elucidated. Therefore, we synthesized the enantiomer of
psychosine (ent-psy) to use as a probe to distinguish between
protein-psy (stereo-specific enantioselective) or membrane-psy (stereo-insensitive nonenantioselective) interactions. The enantiomer of
psychosine has equal or greater toxicity compared with psy, suggesting that psy exerts its toxicity through a nonenantioselective mechanism. Finally, in this study we demonstrate that psy and ent-psy localize to
lipid rafts, perturb natural and
artificial membrane integrity, and inhibit
protein Kinase C translocation to the plasma membrane. Although other mechanisms may play a role in disease, these data strongly suggest that psy exerts its effects primarily through membrane perturbation rather than through specific
protein-psy interactions.