Inhibition of calcium‐activated, phospholipid‐dependent protein kinase (protein kinase C) activity in sphingolipidoses

Abstract

Sphingolipidoses arise as a consequence of a deficiency of specific lysosomal enzymes involved in the catabolism of particular sphingolipids. As a result lipid compounds, specific for each disease, accumulate progressively in tissues in which synthesis and/or degradation are most active, e.g. brain, liver and spleen. Additional changes found in the brain tissue of patients with a neurodegenerative phenotype include neuronal degeneration, brain atrophy, gliosis and demyelination. In these patients, symptoms and signs appear during the first year of life, with loss of developmental qualifications which had been obtained at an earlier age. To date the underlying mechanism linking the sphingolipid accumulation, the histopathology and the functional derangement of cellular processes leading to neurological dysfunction has not been elucidated. Sphingolipids are complex lipids which contain sphingosine (or a related base) as their backbone. Lysosphingolipids differ from their parental sphingolipids by not having the amide-linked fatty acid at the 2-amino position of the sphingoid base. Sphingolipids and lysosphingolipids are degraded by the same catabolic enzymes (Eto et al., 1974), thus a genetic deficiency in one such enzyme results in the accumulation of the two classes of compounds. Lysosphingolipids are toxic to cells, but the mechanism of this cytotoxicity is not known. Results of several recent studies indicate that sphingosine (Hannun et al., 1986), lysosphingotipids (Hannun and Bell, 1987) and gangliosides (Kreutter et al., 1987) inhibit the activity of calcium-activated, phospholipid-dependent protein kinase (protein kinase C). Protein kinase C is a ubiquitous serine and threonine kinase which is tightly linked to the phosphatidylinositol/calcium signal transduction pathway, and has been implicated in the regulation of a large variety of cellular processes (Nishizuka, 1986). In view of the observation that lysosphingolipids modulate protein kinase C activity, by which they could affect cell regulation and cell function, Hannun and Bell (1987) suggested that this finding represents the missing functional link between the accumulation of sphingolipids and the pathogenesis of the sphingolipidoses. This paper provides preliminary evidence in support of this hypothesis.