Role of Sphingomyelin-Ceramide Cycle as a Signaling Pathway in Pediatric Diseases

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Acid sphingomyelinase plays an important role in oxidative stress-induced cellular responses to generate ceramide as an intracellular signaling molecule. Our study suggested a molecular mechanism for activation of acid sphingomyelinase by oxidative stress, X-ray, hydrogen peroxide, and UV. Acid sphingomyelinase may be activated through an oxidative change of C-terminus cysteine residue of the enzyme. The change makes the enzyme to be activated and move to sphingomyelin-rich plasma membrane and generates ceramide, triggering oxidative stress-induced cellular responses. This result demonstrated that acid sphingomyelinase could be a molecular target to create novel treatments of some oxidative stress-related diseases. Next, we revealed some relations between phenotypes and genotypes and between enzyme activity and intracellular cholesterol storage in culture cells of acid sphingomyelinase deficient disease. In addition, we attempted to determine a responsible gene and pathogenesis of Costello syndrome.