The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick diseae.

Abstract

The accumulation of excessive quantities of sphingomyelin in tissues of patients with Niemann-Pick disease was demonstrated by Klenk in 19341, 2 and has been amply confirmed by other investigators.3-5 A study by Crocker and Mays6 indicated that the rate of biosynthesis of sphingomyelin in tissues from these patients appeared to be essentially normal. These findings suggested that the metabolic lesion in this condition might be of a catabolic nature. We have recently obtained evidence for the presence of a specific enzyme in liver tissue which catalyzes the hydrolysis of sphingomyelin.7 The enzyme was partially purified from rat liver tissue, and the products of the reaction were demonstrated to be phosphorylcholine and ceramide. The most highly purified enzyme preparations did not catalyze the hydrolysis of lecithin or phosphatidylethanolamine. Lecithin, however, appeared to be a competitive inhibitor of the reaction. Similar enzymatic activity could be detected in human liver tissue. The present report describes experiments in which the level of the sphingomyelin-cleaving enzyme in liver and kidney tissue obtained from six patients with the classic infantile form of Niemann-Pick disease8 is compared with the values found in a liver biopsy sample from a normal human adult and liver and kidney tissue of patients with various other disorders. Materials and Methods.-Sphingomyelin labeled with C14 in the methyl carbon atoms of the choline portion of the molecule was synthesized as described previously.7 Samples of liver and kidney tissue were homogenized in 10 vol of 0.25 M sucrose with an all-glass TenBroeck homogenizer and centrifuged at 600 X g for 12 min. Suitable aliquots of the supernatant suspensions were

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

“…2 Niemann Pick disease type A (NPA) is a sphingolipidosis caused by loss of function mutations in the gene SMPD1 encoding for the acid sphingomyelinase (ASM). 5 This enzyme catalyzes sphingomyelin (SM) conversion into ceramide in lysosomes. 6 As a result of ASM deficiency, cells from NPA patients accumulate SM in their lysosomes.…”

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

“…[43][44][45][46][47][48] The sphingomyelin pathways have garnered particular attention considering that NiemannPick disease is the result of a deficiency in acidic sphingomyelinase. 49 In addition, the availability of SMase knockout mouse models has enabled investigators to monitor the effect of SMase function on apoptosis. 45,48 The sphingomyelin pathway for ceramide generation demonstrates the versatility of effector responses that can be generated by ceramide.…”

Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann–Pick disease

“…3.1.2.12) activity. [1][2][3] Type A NPD presents with failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course that generally leads to death by 3 years of age. In contrast, type B NPD is characterized by hepatosplenomegaly, pulmonary infiltrates leading to frequent respiratory infections, little or no neurological involvement, and survival into adolescence or adulthood.…”