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Peroxisomal participation in psychosine‐mediated toxicity: Implications for Krabbe's disease
Author(s) -
Khan Mushfiquddin,
Haq Ehtishamul,
Giri Shailendra,
Singh Inderjit,
Singh Avtar K.
Publication year - 2005
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20529
Subject(s) - krabbe disease , leukodystrophy , peroxisome , glutathione , myelin , antioxidant , biochemistry , peroxisomal disorder , biology , toxicity , plasmalogen , chemistry , medicine , endocrinology , central nervous system , phospholipid , disease , membrane , gene , enzyme
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 β‐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 β‐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. © 2005 Wiley‐Liss, Inc.