Molecular mechanism of psychosine-induced cell death in human oligodendrocyte cell line.
This study delineates the molecular mechanism underlying psychosine-induced oligodendroglial cell death. An immortalized human oligodendroglial cell line, MO3.13, was treated with exogenous psychosine (beta-galactosylsphingosine), a toxic metabolite that accumulates in the tissues of patients with Krabbe's disease. The mode of cell death induced by psychosine was found to be apoptotic, as revealed by different apoptotic markers viz., TUNEL, DNA fragmentation and caspase cleavage/activation. The action of psychosine was redox sensitive, as measured by changes in mitochondrial membrane potential (psidelta), and this effect of psychosine could be reversed by pre-treatment with the antioxidant molecules N-acetyl-l-cysteine or pro-cysteine. Psychosine directly affects the mitochondria as revealed by the activation of caspase 9 but not caspase 8. Up-regulation of the c-jun/c-jun N-terminal kinase pathway by psychosine leads to the induction of AP-1 and, at the same time, psychosine also down-regulates the lipopolysaccharide-induced NF-kappaB transactivation. These observations indicate that the mechanism of action of psychosine is, through the up-regulation of AP-1, a pro-apoptotic pathway as well as, through the down-regulation of the NF-kappaB pathway, an antiapoptotic pathway.
Haq
Ehtishamul
E
Department of Pediatrics, Medical University of South Carolina, USA.
Giri
Shailendra
S
Singh
Inderjit
I
Singh
Avtar K
AK
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D007965:Leukodystrophy, Globoid Cell / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011609:Psychosine / Q000633:toxicity*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D000975:Antioxidants; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D011609:Psychosine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D005978:Glutathione