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Ruggero De Maria^*, Maria Rita Rippo^*, Edward H. Schuchman, and Roberto Testi^*

From the ^* Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," 00133 Rome, Italy; and the Department of Human Genetics and Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York 10029

Ceramides deriving from sphingomyelin hydrolysis are important mediators of apoptotic signals originating from Fas (APO-1/CD95). However, definitive evidence for the role played by individual sphingomyelinases is still lacking. We have analyzed lymphoblastoid cell lines derived from patients affected by Niemann Pick disease (NPD), an autosomal recessive disorder caused by loss-of-function mutations within the acidic sphingomyelinase (ASM) gene. NPD lymphoblasts, which display normal neutral sphingomyelinase activity, fail to activate ASM in response to Fas cross-linking, unlike normal lymphoblasts. NPD lymphoblasts also fail to accumulate GD3 ganglioside, a downstream mediator of ceramide-induced cell death (De Maria, R., L. Lenti, F. Malisan, F. D'Agostino, B. Tomassini, A. Zeuner, M.R. Rippo, R. Testi. 1997. Science. 277:1652–1655), and display a substantially inefficient apoptosis after Fas cross-linking. Inefficient apoptosis is due to lack of ASM activity, because proximal signaling from Fas in NPD lymphoblasts is not impaired and apoptosis can be efficiently triggered by passing the ASM defect with exogenous ceramides. Moreover, mannose receptor–mediated transfer of ASM into NPD lymphoblasts rescues their ability to transiently activate ASM, accumulate GD3, and rapidly undergo apoptosis after Fas cross-linking. These results provide definitive genetic evidence for the role of ASM in the progression of apoptotic signals originating from Fas.

Abbreviations used: ASM, acidic sphingomyelinase; CHO, Chinese hamster ovary; HPTLC, high performance thin layer chromatography; M6P, D-mannose-6-phosphate; NPD, Niemann Pick disease; NSM, neutral sphingomyelinase; PCho, phosphocholine; PC-PLC, phosphatidylcholine-specific phospholipase C.

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