Metabolism of Psychosine in SV40-Transformed Schwann Cell Lines

Abstract

The sphingolipidoses constitute a group of neurodegenerative diseases in which there is a deficiency in a specific lysosomal hydrolase for sphingolipids, and therefore patients with these disorders accumulate certain related lipids in various tissues; although the accumulation of sphingolipid per se apparently is not cytotoxic to the nervous system. For example, Suzuki et al. (1) showed that while galactosylceramide induced nonspecific inclusions in macrophages, it was not toxic to the central nervous system. On the other hand, Taketomi and Nishimura (2) showed that a lysosphingolipid, psychosine (galactosylsphingosine), was highly cytotoxic. These findings suggest that psychosine, which accumulates in the central nervous system of patients with Krabbe’s disease, is responsible for the severe demyelination that is characteristic of such patients (3,4). The accumulation of psychosine is also observed in the nervous systems of twitcher mice, an authentic animal model of Krabbe1s disease (5,6). Patients with Krabbe’s disease and twitcher mice share a common defect in the lysosomal galactosylceramide beta-galactosidase (4,5). How the lack of this enzyme results in the accumulation of psychosine is not known. In this report, we investigate the synthesis of psychosine and its cytotoxicity in SV40-transformed Schwann cell lines from normal and twitcher mice.