Peroxisomal participation in psychosine-mediated toxicity: implications for Krabbe's disease.

Abstract

Psychosine (galactosylsphingosine) accumulation in globoid cell leukodystrophy (Krabbe's disease) results in the loss of myelin and oligodendrocytes. To understand the role of psychosine toxicity in Krabbe's disease, we examined the effects of psychosine on peroxisomal functions and their relationship with reactive oxygen species. Rat C(6) glial cells were treated with psychosine with and without cytokines. Peroxisomal beta-oxidation was significantly inhibited and very long chain fatty acid levels and free radicals were increased in treated cells. Furthermore, psychosine treatment decreased glutathione and ATP levels, plasmalogen content, and expression of alkyl-DHAP synthase. Brain tissue of twitcher mice (animal model of Krabbe's) had decreased beta-oxidation activity, low glutathione, and reduced plasmalogens. Psychosine treatment of rat primary oligodendrocytes inhibited peroxisomal activities. Psychosine-mediated loss of peroxisomal function and free radical production was inhibited with the antioxidant N-acetylcysteine in glial cells. Our results suggest that inhibition of peroxisomal functions and increased free radical production by psychosine may be partly responsible for oligodendrocyte and myelin loss observed in the Krabbe's brain, and that antioxidant therapy may be useful in the treatment of Krabbe's disease.