Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed.

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Metabolic and cellular bases of sphingolipidoses

Biochemical Society Transactions ◽

10.1042/bst20130083 ◽

2013 ◽

Vol 41 (6) ◽

pp. 1562-1568 ◽

Cited By ~ 33

Author(s):

Konrad Sandhoff

Keyword(s):

Binding Proteins ◽

Membrane Lipids ◽

Lipid Extraction ◽

Cholesterol Content ◽

Lipid Binding ◽

Acid Sphingomyelinase ◽

Permeability Barrier ◽

Activator Proteins ◽

Type C ◽

Niemann Pick

Lysosomes are cellular stomachs. They degrade macromolecules and release their components as nutrients into the cytosol. Digestion of sphingolipids and other membrane lipids occurs at luminal intraendosomal vesicles and IMs (intraendosomal membranes). Sphingolipid and membrane digestion needs catabolic hydrolases with the help of lipid-binding proteins [SAPs (sphingolipid activator proteins)] and anionic lipids such as BMP [bis(monoacylglycero)phosphate]. Inherited defects of hydrolases or SAPs or uptake of cationic amphiphilic drugs cause lipid accumulation, eventually leading to death, especially in inherited sphingolipid storage diseases. IMs are formed during endocytosis and their lipid composition is adjusted for degradation. Their cholesterol content, which stabilizes membranes, decreases and the level of negatively charged BMP, which stimulates sphingolipid degradation, increases. At the level of late endosomes, cholesterol is transported out of the luminal vesicles preferentially by cholesterol-binding proteins, NPC (Niemann–Pick type C)-2 and NPC-1. Their defects lead to an endolysosomal accumulation of cholesterol and sphingolipids in Niemann–Pick type C disease. BMP and ceramide stimulate NPC-2-mediated cholesterol transfer, whereas sphingomyelin inhibits it. Anionic membrane lipids also activate sphingomyelin degradation by ASM (acid sphingomyelinase), facilitating cholesterol export by NPC-2. ASM is a non-specific phospholipase C and degrades more than 23 phospholipids. SAPs are membrane-perturbing proteins which solubilize lipids, facilitating glycolipid digestion by presenting them to soluble catabolic enzymes at acidic pH. High BMP and low cholesterol levels favour lipid extraction and membrane disintegration by saposin A and B. The simultaneous inherited defect of saposins A–D causes a severe membrane and sphingolipid storage disease, also disrupting the water permeability barrier of the skin.

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Faculty Opinions recommendation of Liver and skin histopathology in adults with acid sphingomyelinase deficiency (Niemann-Pick disease type B).

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717597820.793453174 ◽

2012 ◽

Author(s):

Guadalupe Garcia-Tsao

Keyword(s):

Disease Type ◽

Acid Sphingomyelinase ◽

Type B ◽

Sphingomyelinase Deficiency ◽

Niemann Pick Disease ◽

Niemann Pick ◽

Pick Disease

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Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

International Journal of Molecular Sciences ◽

10.3390/ijms22147292 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7292

Author(s):

Luca Marsili ◽

Jennifer Sharma ◽

Alberto J. Espay ◽

Alice Migazzi ◽

Elhusseini Abdelghany ◽

...

Keyword(s):

Spinocerebellar Ataxia Type ◽

Niemann Pick Disease ◽

Whole Exome ◽

Heterozygous Variant ◽

History Of ◽

Ataxia Syndrome ◽

Niemann Pick

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

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Comparative Effects of Recombinant Acid Sphingomyelinase Administration by Different Routes in Niemann-Pick Disease Mice

Experimental Animals ◽

10.1538/expanim.53.417 ◽

2004 ◽

Vol 53 (5) ◽

pp. 417-421 ◽

Cited By ~ 7

Author(s):

Jae-Sung BAE ◽

Kwang-Ho JANG ◽

Edward H. SCHUCHMAN ◽

Hee Kyung JIN

Keyword(s):

Acid Sphingomyelinase ◽

Niemann Pick Disease ◽

Niemann Pick ◽

Pick Disease

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Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick disease

The Journal of Pediatrics ◽

10.1016/j.jpeds.2006.06.034 ◽

2006 ◽

Vol 149 (4) ◽

pp. 554-559 ◽

Cited By ~ 47

Author(s):

Melissa P. Wasserstein ◽

Alan Aron ◽

Scott E. Brodie ◽

Calogera Simonaro ◽

Robert J. Desnick ◽

...

Keyword(s):

Acid Sphingomyelinase ◽

Intermediate Phenotype ◽

Sphingomyelinase Deficiency ◽

Niemann Pick Disease ◽

Niemann Pick ◽

Pick Disease

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Acid and neutral sphingomyelinases: roles and mechanisms of regulation

Biochemistry and Cell Biology ◽

10.1139/o03-091 ◽

2004 ◽

Vol 82 (1) ◽

pp. 27-44 ◽

Cited By ~ 224

Author(s):

Norma Marchesini ◽

Yusuf A Hannun

Keyword(s):

Nitric Oxide ◽

Molecular Mechanisms ◽

Caveolin 1 ◽

Niemann Pick Disease ◽

Extracellular Stimuli ◽

Niemann Pick ◽

Hydrolysis Of ◽

Pick Disease

Ceramide, an emerging bioactive lipid and second messenger, is mainly generated by hydrolysis of sphingomyelin through the action of sphingomyelinases. At least two sphingomyelinases, neutral and acid sphingo myelinases, are activated in response to many extracellular stimuli. Despite extensive studies, the precise cellular function of each of these sphingomyelinases in sphingomyelin turnover and in the regulation of ceramide-mediated responses is not well understood. Therefore, it is essential to elucidate the factors and mechanisms that control the activation of acid and neutral sphingomyelinases to understand their the roles in cell regulation. This review will focus on the molecular mechanisms that regulate these enzymes in vivo and in vitro, especially the roles of oxidants (glu ta thi one, peroxide, nitric oxide), proteins (saposin, caveolin 1, caspases), and lipids (diacylglycerol, arachidonic acid, and ceramide).Key words: sphingomyelinase, ceramide, apoptosis, Niemann-Pick disease, FAN (factor associated with N-SMase activation).

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Infusion of recombinant human acid sphingomyelinase into Niemann‐Pick disease mice leads to visceral, but not neurological, correction of the pathophysiology

The FASEB Journal ◽

10.1096/fj.00-0014com ◽

2000 ◽

Vol 14 (13) ◽

pp. 1988-1995 ◽

Cited By ~ 100

Author(s):

Silvia R. P. Miranda ◽

Xingxuan He ◽

Calogera M. Simonaro ◽

Shimon Gatt ◽

Arie Dagan ◽

...

Keyword(s):

Acid Sphingomyelinase ◽

Niemann Pick Disease ◽

Human Acid ◽

Niemann Pick ◽

Pick Disease

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Alveolar lipoproteinosis in an acid sphingomyelinase-deficient mouse model of Niemann-Pick disease

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00258.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. L518-L525 ◽

Cited By ~ 32

Author(s):

Machiko Ikegami ◽

Rajwinder Dhami ◽

Edward H. Schuchman

Keyword(s):

Alveolar Macrophages ◽

Pulmonary Inflammation ◽

Acid Sphingomyelinase ◽

Deficient Mouse ◽

Niemann Pick Disease ◽

Surfactant Inhibition ◽

Niemann Pick ◽

Surfactant Composition ◽

Pick Disease

Types A and B Niemann-Pick disease (NPD) are lipid storage disorders caused by the deficient activity of acid sphingomyelinase (ASM). In humans, NPD is associated with the dysfunction of numerous organs including the lung. Gene targeting of the ASM gene in transgenic mice produced an animal model with features typical of NPD, including pulmonary inflammation. To assess mechanisms by which ASM perturbed lung function, we studied lung morphology, surfactant content, and metabolism in ASM-deficient mice in vivo. Pulmonary inflammation, with increased cellular infiltrates and the accumulation of alveolar material, was associated with alterations in surfactant content. Saturated phosphatidylcholine (SatPC) content was increased twofold, and sphingomyelin content was increased 5.5-fold in lungs of the ASM knockout (ASMKO) mice. Additional sphingomyelin enhanced the sensitivity of surfactant inhibition by plasma proteins. Clearance of SatPC from the lungs of ASMKO mice was decreased. Catabolism of SatPC by alveolar macrophages from the ASMKO mouse was significantly decreased, likely accounting for decreased pulmonary SatPC in vivo. In summary, ASM is required for normal surfactant catabolism by alveolar macrophages in vivo. Alterations in surfactant composition, including increased sphingomyelin content, contributed to the abnormal surfactant function observed in the ASM-deficient mouse.

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