Lysosphingolipids Inhibit Protein Kinase C: Implications for the Sphingolipidoses

TLDR

Accumulation of lysosphingolipids impairs signal transduction essential for neural functions, ultimately causing cell death. The study tests whether lysosphingolipid inhibition of protein kinase C links sphingolipid accumulation to the pathogenesis of sphingolipidoses such as Krabbe's and Gaucher's disease. Lysosphingolipids potently and reversibly inhibit protein kinase C activity and phorbol ester binding in vitro and in human platelets, with inhibition dependent on surface dilution and occurring at molar percentages comparable to those needed for activation by phosphatidylserine and diacylglycerol.

Abstract

Lysosphingolipids potently and reversibly inhibited protein kinase C activity and binding of phorbol dibutyrate in vitro and in human platelets. As with activation of protein kinase C by phosphatidylserine and sn -1,2-diacylglycerol, inhibition was subject to surface dilution. Accordingly, inhibition in mixed micelle assays was dependent on the molar percentage of lysosphingolipids rather than the bulk concentration. Lysosphingolipids inhibited protein kinase C activity at molar percentages similar to those required for activation by phosphatidylserine and sn -1,2-diacylglycerol. Since lysosphingolipids accumulate in Krabbe's disease, Gaucher's disease, and other sphingolipidoses, the hypothesis that lysosphingolipid inhibition of protein kinase C represents the missing functional link between the accumulation of sphingolipids and the pathogenesis of these disorders appears to unify existing data. The accumulation of lysosphingolipids would cause progressive dysfunction of signal transduction mechanisms vital for neural transmission, differentiation, development, and proliferation and would eventually lead to cell death.