Acid sphingomyelinase, cell membranes and human disease: Lessons from
Edward H. Schuchman*
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, Icahn Medical Institute, Floor 14 Room 14-20A, 1425 Madison Avenue, New York, NY 10029, USA
a r t i c l ei n f o
Received 29 October 2009
Accepted 24 November 2009
Available online 26 November 2009
Edited by Sandro Sonnino
a b s t r a c t
Acid sphingomyelinase (ASM) plays an important role in normal membrane turnover through the
hydrolysis of sphingomyelin, and is one of the key enzymes responsible for the production of cera-
mide. ASM activity is deficient in the genetic disorder Types A and B Niemann–Pick disease (NPD).
ASM knockout (ASMKO) mice were originally constructed to study this disorder, and numerous
defects in ceramide-related signaling have been shown. Studies in these mice have further sug-
gested that ASM may be involved in the pathogenesis of several common diseases through the reor-
ganization of membrane microdomains. This review will focus on the role of ASM in membrane
biology, with a specific emphasis on what a rare genetic disorder (NPD) has taught us about more
? ? 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
The fluid mosaic model of the cell membrane, first proposed in
the early 1970s, suggested that membranes exist in a disorder sta-
tus without significant selectivity . This concept rapidly estab-
lished itself as dogma, although in recent years a body of
literature has shown that the cell membrane is, in fact, composed
of small ‘‘microdomains” that exist in a liquid-ordered phase .
These domains are static within the membrane, and can coalesce
and reorganize in response to various stimuli. Several laboratories
also have shown that sphingolipids and cholesterol associate with
these microdomains, and that these associations are integral to
membrane function. The sphingolipid and cholesterol-enriched
membrane microdomains have been referred to as lipid ‘‘rafts”
[3,4]. Despite a growing literature, the concept of membrane
microdomains has remained controversial, principally because
data demonstrating the existence of these domains in vivo is lim-
ited. As summarized below, studies of one sphingolipid hydrolase,
acid sphingomyelinase (ASM), specifically those using ASM knock-
out mice (ASMKO), have provided some of the strongest evidence
to date supporting the concept of membrane microdomains in
vivo. They also have highlighted the important role of this enzyme
in normal cell function and the pathogenesis of many common
Numerous reviews are available on the function of ASM in cell
signaling, as well as on its involvement in specific human diseases
(e.g. [5–7]). The purpose of this review is to summarize informa-
tion regarding the role of ASM in membrane biology. In order to
provide a biological context, a systems approach will be used.
Much of this information comes from studies using ASMKO mice,
which were originally created as a model of the human genetic dis-
order, Types A and B Niemann–Pick disease (NPD) . A brief back-
ground on ASM and NPD is provided below, followed by a
summary of studies using the ASMKO mice that reveal the function
of ASM on cell membranes. Despite the fact that NPD was de-
scribed nearly a century ago and ASM was identified over 40 years
ago, this literature has mostly emerged during the past decade. It is
therefore an evolving field, but one that has already integrated di-
verse scientific disciplines, ranging from physicians, biophysicists,
lipid biochemists and signal transduction biologists, and identified
ASM as a target for numerous, common diseases.
1.1. Acid sphingomyelinase: historical perspective
Acid sphingomyelinase (ASM; EC 184.108.40.206) is one member of a
family of enzymes that catalyzes the breakdown of sphingomyelin
by cleavage of the phosphorylcholine linkage, thereby producing
ceramide. The existence of such a ‘‘sphingomyelin cleaving en-
zyme” was first demonstrated in 1938 by the pioneering work of
Thannhauser, Reichel and colleagues . During the ensuing 25
years, several similar enzymatic activities were identified that dif-
fered mostly in their tissue distribution and pH optimum. The first
0014-5793/$36.00 ? 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
* Fax: +1 212 849 2447.
E-mail address: Edward.Schuchman@mssm.edu
FEBS Letters 584 (2010) 1895–1900
journal homepage: www.FEBSLetters.org
clear description of a sphingomyelin hydrolase that worked opti-
mally at acidic pH (i.e., ASM) was made by Gatt and colleagues in
1963 . In addition to ASM, at least three other sphingomyelin-
ases have been described in mammalian cells that vary in their pH
optimum and co-factor dependence [11–13]. While these enzymes
and an existing de novo synthetic pathway are alternative mecha-
nisms for ceramide generation, each with their own implications
on cell signaling and disease, this review will specifically focus
on the contributions of ASM.
By the late 1960s, researchers reported that the deficiency of
ASM was responsible for the rare, recessively inherited lysosomal
storage disorder, Niemann–Pick disease (Types A and B NPD; see
below), stimulating intensive efforts to purify and characterize it
[14–18]. Early investigations identified ASM as a glycoprotein,
and because the pH optimum of the enzyme in vitro was between
4.5 and 5.0, coupled with the fact that the majority of storage
material in NPD patients was found in lysosomes and/or late endo-
somes, the enzyme was classified as a lysosomal protein . The
cDNA and gene encoding ASM (designated SMPD1) were cloned in
1989 and 1992, respectively [20,21]. They predicted a 629 amino
acid polypeptide that included a 46 amino acid signal peptide re-
gion and two in-frame ATG initiation sites. Mutation analysis in
NPD patients showed that both ATG initiation sites were functional
in vivo .
SDS–PAGE analysis of ASM purified from various sources re-
vealed an estimated molecular weight of ?72 kDa; enzymatic de-
glycosylation reduced the molecular weight to ?60 kDa [14,23].
Processing studies performed in COS-1 cells further showed that
ASM was synthesized as a ?75-kDa ‘‘prepro” protein that was traf-
ficked to lysosomes. Interestingly, in these same studies, a 57 kDa
secreted form of ASM also was identified . Subsequent charac-
terization studies revealed that 5 of 6 N-glycosylation sites of the
enzyme were occupied , and that the oligosaccharide side
chains contained mannose-6-phosphate residues, typical of lyso-
somal proteins . In addition, the disulfide bond structure of
ASM was characterized , and it was found the terminal cys-
teine at amino acid residue 629 was the only cysteine not involved
in intra-molecular disulfide linkages. In fact, this terminal cysteine
residue must be removed to obtain full ASM activity , and it is
thought that the retention of this residue in the mature protein
may lead to the formation of inactive, higher molecular weight
Around this time, Tabas and co-workers identified a zinc-
dependant, secreted form of ASM that also was encoded by the
SMPD1 gene . They proposed that the apparent differences in
zinc-dependence of the lysosomal and secreted ASM forms was
due to differential cellular trafficking that either exposed or
sequestered the enzyme from cellular pools of zinc . It is note-
worthy that a zinc-activated, secreted form of ASM was first iden-
tified in plasma in the late 1980s, although its biological function
remained unknown . There is now growing evidence suggest-
ing that this ASM form may play a role in atherosclerosis, cell sur-
face signaling and host inflammation (see below) [5,6,32].
Interestingly, the SMPD1 gene is within an ‘‘imprinted” region of
the human genome (chromosomal region 11p15.4), and is prefer-
entially expressed from the maternal chromosome (i.e., paternally
imprinted) [33,34]. This form of genetic regulation is typical of
genes that play an important role in development.
Until the mid-1990s, interest in ASM was limited primarily to
researchers studying NPD. At this time, ASM knockout (ASMKO)
mice were constructed , and were found to be resistant to radi-
ation  and other forms of stress-induced apoptosis (see below).
These observations introduced ASM to many new investigators and
opened new avenues of research. To date, ASM inhibition (using
siRNA, pharmacologic inhibitors, or using NPD cells or KO mice)
has been shown to render cells and animals resistant to the apop-
totic effects of diverse stimuli, including but not limited to Fas/
CD95 , ischemia , radiation [35,38], chemotherapy ,
and TNFalpha . This effect of ASM has been attributed to local
changes in sphingomyelin, ceramide and cholesterol content, and
ultimately reorganization of membrane microdomains.
Another significant advancement in ASM research was the
large-scale purification of the recombinant enzyme from the media
of genetically engineered Chinese hamster ovary cells . With
the availability of recombinant ASM, good antibodies against the
enzyme also soon became available, stimulating new avenues of
research. Importantly, several investigators showed by immunocy-
tochemistry that when cells were exposed to various forms of
stress, the location of this protein changed from primarily lyso-
somal/endosomal to the cell surface (e.g. Ref. ). This observa-
tion marked a watershed in ASM biology, as it is at the outer
leaflet of the cell membrane where ASM initiates cell signaling,
and thus exerts its impact on the pathogenesis of a diverse group
The precise mechanism by which ASM, which normally resides
within lysosomes, is translocated to the cell surface remains un-
known. Recently, Zeidan et al. showed that phosphorylation of a
specific serine residue on ASM (S508) by PKCdelta is required for
its activation in response to UV irradiation and movement to the
membrane [43,44]. These investigators suggested that the phos-
phorylation occurs within the lysosomes, although it is also possi-
ble that a cytosolic pool of ASM serves as the substrate for
PKCdelta, or that phosphorylation occurs within some other com-
partment at or near the cell surface. Deciphering the precise traf-
ficking and processing of ASM during cell signaling is likely to be
a fruitful area for future research.
1.2. Types A and B NPD: brief overview
As noted above, until recently, interest into the biology of ASM
was due to its role in the genetic disorder, Types A and B NPD. Both
forms of this disorder are caused by recessive mutations in the
SMPD1 gene encoding ASM. Type A NPD is the infantile form of
ASM deficiency, characterized by a rapidly progressive neurode-
generative course that leads to death by age 2–3. In contrast, Type
B NPD is the later-onset form in which patients exhibit little or no
neurological symptoms, but may have severe and progressive vis-
ceral organ abnormalities, including hepatosplenomegaly, pul-
different clinical presentations of Types A and B NPD are likely
due to small differences in the amount of residual, functional
ASM activity .
The first patient with NPD (Type A) was described in 1914 by
the German pediatrician, Albert Niemann, and by the 1930s the
primary lipid accumulating in these individuals was identified as
sphingomyelin [47,48]. It is now known that secondary to sphingo-
myelin storage, other lipids, including cholesterol and gangliosides,
also accumulate in these patients, leading to many cellular abnor-
malities . While most of the clinical findings in NPD are likely
related to lipid storage in lysosomes and/or endosomes, recent
data revealing the important role ASM in membrane formation
and function  suggests that defective function of the enzyme
at the cell surface also could contribute to the pathophysiology
of NPD as well.
Due to the fact that NPD is an extremely rare genetic disorder,
ASMKO mice were created in the mid-1990s to further understand
the biology of this disease . These animals have been extensively
used for the pre-clinical evaluation of enzyme replacement ther-
apy, gene therapy and stem cell transplantation for NPD patients,
leading to the first clinical trials of enzyme replacement using re-
combinant ASM. In addition, the ASMKO mice have been an invalu-
able tool for studying sphingolipid metabolism, revealing the
E.H. Schuchman/FEBS Letters 584 (2010) 1895–1900
important and unexpected role of this enzyme in diverse cellular
events . The remainder of this review will focus on studies from
2. ASM and cell membranes – overview
The role of ASM in cell signaling is tightly linked to its ability to
reorganize the plasma membrane. As noted above, the central the-
sis of the classic, fluid mosaic model of membranes is that proteins
float freely in the lipid bilayer . However, protein interactions
within the membrane are far more complex than originally pro-
posed, and sphingolipids (particularly sphingomyelin and cera-
increasing ‘‘order” to isolated membrane regions . The most
prevalent lipid in the outer leaflet of the membrane is sphingomy-
elin, which is hydrolyzed to ceramide by ASM and other sphing-
omyelinases . Ceramide molecules in the lipid bilayer are
known to interact with each other at the exclusion of other lipids,
leading to the formation of isolated lipid ‘‘microdomains” .
Subsequently, either by changing the physical properties of the
membrane or by direct ceramide–protein interactions, these cera-
mide-enriched microdomains are thought to enhance the density
of proteins, which promotes receptor dimerization as well as other
protein–protein interactions . Current theory postulates that
ASM serves to reorganize the cell surface and activate signaling
proteins within these microdomains, thus enhancing, or possibly
lowering, the threshold for downstream signaling (for review, see
Data showing that ASM functions at the cell surface were ini-
tially considered counter-intuitive since its housekeeping role re-
sides within lysosomes and its pH optimum in vitro was clearly
acidic. However, an important observation was made in 1998,
when it was shown that the secreted form of ASM could degrade
sphingomyelin to ceramide within LDL particles at physiologic
pH, suggesting that the in vitro pH optimum might not predict
in vivo function . In addition, there have been recent reports
demonstrating acidified microenvironments at the cell surface,
and some of these reports have linked such microenvironments
to lipid microdomains , the very site of ASM action.
components that provide
3. ASM and cell membranes: a systems approach
As noted above, during the past decade a body of literature has
emerged, mostly from studies in the ASMKO mice, that clearly dem-
onstrates a function for ASM at the cell surface and/or in the reorga-
nization of membrane microdomains.These findingshave important
implications for many diseases, including NPD, and have suggested
new treatment options. In the section below recent findings from
the ASMKO mice will be summarized according to five major organ
systems: brain, lung, heart, gonads,andskin, sincethese fivesystems
represent the majority of the literature published to date with an
obvious link to membrane biology and/or disease mechanisms. In
continue to emerge, expanding our understanding of thisenzyme, its
role in membrane biology, and identifying new molecular targets for
therapy. It is not the intention of this review to comprehensively as-
sess the role of ASM in the pathogenesis of disease, as this has been
accomplished in other reviews (e.g. ). Rather, the goal below is to
summarize specific, recent examples that provide direct evidence for
a function of ASM on the cell membrane.
Given the severe, neurodegenerative phenotype of Type A NPD,
it has been presumed for nearly a century that ASM should have a
major influence on neuronal function. However, due to the paucity
of human materials for research, until recently the precise cellular
and biochemical abnormalities in the brains of NPD patients,
including changes in the cell membranes, have not been studied
in detail. Recently, the ASMKO mice have provided a new resource
to study neural pathology related to ASM, shedding new light on
the enzyme’s function in neurons and other neural cells. For exam-
ple, using these mice Scandroglio et al. showed that in addition to
sphingomyelin, ASMKO brain tissue and cultured cerebellar gran-
ule neurons had increased gangliosides, mainly GM2 and GM3.
Gangliosides have diverse and important functions in the brain,
and changes in these lipids were not intuitively expected as a re-
sult of ASM deficiency. In contrast, cholesterol and glycerophos-
sphingomyelin, remained unchanged in the brains of these animals
Of specific relevance to this review, these investigators also
found that a higher detergent to protein ratio was required to
prepare detergent-resistant membrane fractions in ASMKO mouse
brains as compared to wild-type animals. This finding suggested a
reduction in fluidity of specific membrane areas due to the
accumulation of sphingolipids, and provided some of the first di-
rect evidence that ASM deficiency alters the lipid composition of
the plasma membrane . Similarly, Galvan et al. demonstrated
increased sphingomyelin in detergent-resistant membranes of
cultured ASMKO neurons that led to an aberrant distribution of
GPI-anchored proteins, providing a direct link between lipid
changes, ASM function and membrane embedded signaling pro-
teins. Importantly, increasing sphingomyelin in wild-type neurons
mimicked these defects, whereas reducing this lipid in ASMKO
neurons corrected them . Bianco et al. have also shown that
following activation of the ATP receptor P2X7, microparticle shed-
ding and IL-1beta release from microglia in ASMKO mice was
markedly reduced as compared to normal mice , and Camolet-
to et al. reported that ASMKO synaptic membranes had higher lev-
els of sphingomyelin and sphingosine that was associated with
enhanced interaction of the docking molecules, Munc18 and syn-
taxin1 . Overall, these findings provide the first molecular data
demonstrating the importance of ASM in neural cell membrane
organization and function, and shed new light into the pathogenic
mechanisms underlying Type A NPD and other neurodegenerative
diseases. Given the importance of membranes in neural cell com-
munication, migration and survival, and the fact that ASM is ubiq-
uitously expressed at high levels throughout the brain, new and
important roles for this enzyme in neural function are likely to
be uncovered in the future.
By its nature, infection requires a close interaction of pathogens
(e.g. bacteria and virus) with membranes of the target cell. During
the past several years, a large literature has evolved using the ASM-
KO mice illustrating the important role of ASM in this process. Ini-
tial studies by Grassme and Hauck showed that inhibition of ASM
(pharmacologically or genetically in ASMKO mice) prevented the
entry of Neisseria gonorrhoeae into epithelial  and phagocytic
cells . Interestingly, subsequent studies with Listeria monocyt-
ogenes showed that ASMKO mice are ?100-fold more sensitive to
infection with this bacterium than wild-type mice , presum-
ably because the ASM-deficient macrophages were unable to kill
the bacteria and restrict their growth. These latter data suggested
a novel function of ASM in infectious biology that directly relates
to its role in controlling the fusion of intracellular phagosomes
with lysosomes, a process that is inherently dependent on the
interaction of vesicle membranes.
E.H. Schuchman/FEBS Letters 584 (2010) 1895–1900
The involvement of ASM has been shown in infection of other
bacteria as well, including Staphylococcus aureus , Salmonella
typhimurium , Escherichia coli , Mycobacterium  and
Pseudomonas aeruginosa . Studies with this latter pathogen
have important implications for patients with systemic infections,
ventilator-associated pneumonia, and cystic fibrosis. Infection of
lung epithelial cells with P. aeuroginosa normally leads to a rapid
activation of ASM that correlates with translocation of the enzyme
to the extracellular leaflet of the cell membrane and the site of bac-
terial infection . The activity of ASM at this site leads to the for-
mation of ceramide-enriched rafts, which are critical for the
internalization of P. aeurginosa into the cells, the induction of cell
death, and the gradual release of inflammatory cytokines. Cera-
mide-enriched membrane domains may regulate internalization
of P. aeurginosa by clustering of the CFTR protein, as it has been
shown that CFTR moves into rafts after infection and that internal-
ization of the pathogen can be prevented by disruption of these
membrane structures . Compromised host response in ASMKO
mice further corroborated the importance of ASM in effective
phagocytosis and eradication of pathogens via membrane modula-
tion . Clearly, the mechanisms by which ASM participates in
infection are variable and pathogen-specific, and highly dependent
on membrane interactions. This literature is rapidly expanding,
and will likely reveal ASM as a potential drug target for numerous
For many years it has been known that Types A and B NPD pa-
tients have abnormal plasma lipid profiles, characterized by in-
creased levels of LDL-cholesterol and triglycerides, and markedly
reduced HDL-cholesterol . However, the precise role of ASM
in lipoprotein assembly and metabolism is unclear, as is its role
in normal cardiac function. An interesting concept of direct rele-
vance to this review has been put forth by Tabas and colleagues,
who suggested that the sphingolipid content of circulating lipopro-
teins controls their propensity to self-assemble and aggregate,
leading to their association with cell membranes and retention
within the arterial wall. For example, Marthe et al.  showed
that the secreted form of ASM (referred to by these workers as S-
SMase) was present in atherosclerotic lesions and bound to specific
components of the subendothelial extracellular matrix. Schissel
et al.  further showed that S-SMase could hydrolyze sphingo-
myelin present in LDL at physiological pH, stimulating subendo-
thelial retentionand aggregation.
observation, as prior to this publication it was assumed that the
only function(s) for ASM were within acidified vesicles such as
lysosomes. The fact that ASM could hydrolyze sphingomyelin at
physiological pH suggested new functions for the enzyme, includ-
ing its potential activity at the cell surface and on membranes.
Devlin et al.  later reproduced this finding by showing
that ASM induced lipoprotein retention and accelerated athero-
sclerotic lesion progression in vivo. Clearly, the pathogenesis of
these events relates to remodeling of the lipoproteins in a way
that results in a propensity towards interactions with the suben-
dothelial cell membrane. Inhibition of this LDL-membrane inter-
action could have important implications in the treatment of
ASM remodeling of the cell membrane also plays an impor-
tant role in other cardiac cell types. For example, Jia et al. 
found that oxotremorine, a muscarinic type 1 receptor agonist,
increased lipid raft clustering in bovine coronary arterial myo-
cytes, leading to formation of a complex of CD38 within ASM
and ceramide-enriched membrane domains. Jin et al.  also
showed a colocalization of lipid rafts with NADPH oxidase sub-
units, gp91 and p47, in endostatin-stimulated coronary endothe-
lial cells. The formation of this lipid raft platform was prevented
by RNAi knockdown of ASM. Thus, reorganization of cell mem-
branes by ASM is likely to play diverse roles in the heart, and
abnormalities in this process could be responsible for several
Fertilization, like infection, is inherently dependent on complex
membrane interactions, and sperm are known to secrete large
amounts of hydrolytic enzymes, including ASM, presumably to
reorganize the membrane of the oocyte and facilitate fertilization
. However, little is known about the specific role of ASM in
germ cell function and fertilization. Of note, Butler et al. performed
one of the first analyses of ASM in gametes using sperm from ASM-
KO mice, and showed elevated levels of sphingomyelin and choles-
terol that resulted in morphologic abnormalities such as kinks and
bends at the midpiece-principle piece junction, leading to reduced
motility . Flow cytometric analysis further revealed that af-
fected spermatozoa had disrupted acrosomal membranes and did
not undergo proper capacitation, as assessed by nitric oxide release
and bilayer translocation of phosphatidylserine. In addition, these
sperm exhibited compromised plasma membranes and mitochon-
drial membrane depolarization. Notably, spermatozoa from the
ASMKO mice regained normal morphology upon incubation in
mild detergent, demonstrating that these defects were a direct
consequence of membrane lipid accumulation . These results
provided in vivo evidence that normal sphingomyelin and choles-
terol metabolism within the sperm membrane is essential for
sperm maturation and function, and that ASM activity plays a crit-
ical role in these events. More recently, ASM also was found to be
an important component of normal oocyte maturation and survival
by modulating ceramide signaling (e.g. ), although the direct
effect of this enzyme on the oocyte membrane has not been eluci-
dated. There also have been sporadic reports in the NPD literature
of reduced fertility among female NPD patients, although the
mechanism remains unknown.
Ceramide plays a critical function in epidermal barrier homeo-
stasis by constituting an integral component of the extracellular
lipid bilayer at the stratum corneum . However, despite the
well documented role of ceramide in this process, the precise
function of ASM in the generation of epidermal ceramide has
not been studied in great detail. In 2000, Schmuth et al. showed
that a subset of NPD patients with severe ASM deficiency demon-
strated abnormal permeability barrier homeostasis, presumably
due to an abnormally low ceramide content . To gain further
mechanistic insights into this finding, these same investigators
investigated the effects of ASM inhibitors, palmitoyldihydrosp-
hingosine and desipramine, on the skin of hairless mice, and
found that inhibitor treatment led to an increase in sphingomye-
lin and a reduction of normal extracellular lamellar membrane
structures in the stratum corneum. In addition, they found a de-
layed barrier recovery after injury. This delay could be overcome
by the topical application of ceramide, indicating that the finding
in NPD patients was likely due to an altered ceramide–sphingo-
myelin ratio rather than sphingomyelin accumulation itself .
Patients with atopic dermatitis also have reduced levels of ASM
(and neutral sphingomyelinase) in their lesions, likely leading to
reduced ceramide levels and the permeability barrier abnormali-
ties characteristic of this disease . While it is apparent that
the normal function of skin relies heavily on the integrity of epi-
dermal cell membranes, the involvement of ASM in this process
awaits further elucidation.
E.H. Schuchman/FEBS Letters 584 (2010) 1895–1900
The study of ASM is an excellent example of how diverse fields
of biology can co-exist for long periods of time without interaction,
and then unexpectedly coalesce to open productive and insightful
new areas of research. The first case of NPD was described nearly a
century ago, and the first isolation of ASM was achieved nearly five
decades ago. Simultaneous with this research, biochemists defined
the principles of membrane structure and function, without signif-
icant interactions with pediatricians and other scientists studying
this enzyme and rare genetic disease. Beginning in the late
1990s, however, stimulated by reagents generated for the study
of NPD (e.g. ASMKO mice, SPMD1 gene, ASM antibodies, and re-
combinant ASM), a small group of biologists examining the role
of sphingolipids in cell signaling became interested in this enzyme,
and subsequently defined a new role in the organization of mem-
brane microdomains. This has not only shed new light into biology
of NPD but, importantly, identified potential new roles for this en-
zyme in numerous other common diseases, including cancer, dia-
betes, depression, dementia, cardiac disease and others. In turn,
these findings have suggested new therapeutic options based on
either inhibiting ASM function or overexpressing ASM at specific
target sites. It is likely that this will remain a fruitful area of re-
search for the foreseeable future, and will lead to new treatment
options for these devastating disorders. While it is unfortunate that
these diverse areas of biology could not come together sooner,
with new technologies and rapid sharing of literature it is likely
that such cross-fertilization will occur at a much faster pace in
the future, and biomedical science will benefit greatly from it.
Conflict of interest statement
Dr. Schuchman is an inventor on a patent owned by the Mount
Sinai School of Medicine that has been licensed to the Genzyme
Corporation for the development of enzyme replacement therapy
for NPD. Also, Dr. Schuchman is a consultant and receives research
grants from Genzyme for the study of ASM and NPD.
E.H.S. would like acknowledge the contributions of the many
students, fellows and scientists who have worked in his laboratory
on the biology of ASM and NPD, as well as the patients and families
who have contributed valuable research materials. He would also
like to acknowledge the specific contribution of Dr. Ching-Yin Lee
for assistance with the preparation of this manuscript. ASM and
NPD research in Dr. Schuchman’s laboratory is supported by the
National Institutes of Health, Genzyme Corporation, and National
Niemann–Pick Disease Foundation.
 Singer, S.J. and Nicolson, G.L. (1972) The fluid mosaic model of the structure of
cell membranes. Science. 175, 720–731.
 Jacobson, K., Sheets, E.D. and Simson, R. (1995) Revisiting the fluid mosaic
model of membranes. Science 268, 1441–1442.
 Simons, K. and Ikonen, E. (1997) Functional rafts in cell membranes. Nature
 Anderson, R.G. and Jacobson, K. (2002) A role for lipid shells in targeting
proteins to caveolae, rafts, and other lipid domains. Science 296, 1821–1825.
 Smith, E.L. and Schuchman, E.H. (2008) The unexpected role of acid
sphingomyelinase in cell death and the pathophysiology of common
diseases. FASEB J. 22, 3419–3431.
 Jenkins, R.W., Canals, D. and Hannun, Y.A. (2009) Roles and regulation of
secretory and lysosomal acid sphingomyelinase. Cell. Signal. 21, 836–846.
 Alessenko, A.V. (2000) The role of sphingomyelin cycle metabolites in
transduction of signals of cell proliferation, differentiation and death.
Membr. Cell Biol. 13, 303–320.
 Horinouchi, K., Erlich, S., Perl, D.P., Ferlinz, K., Bisgaier, C.L., Sandhoff, K.,
Desnick, R.J., Stewart, C.L. and Schuchman, E.H. (1995) Acid sphingomyelinase
deficient mice. a model of types A and B Niemann–Pick disease. Nat. Genet. 10,
 Thannhauser, S.J., Reichel, M. and Grattan, J.F. (1938) The effect of ascorbic acid
on beta-glycerophosphate. Biochem. J. 32, 1163–1165.
 Gatt, S. (1963) Enzymic hydrolysis and synthesis of ceramide. J. Biol. Chem.
 Levade, T., Andrieu-Abadie, N., Ségui, B., Augé, N., Chatelut, M., Jaffrézou, J.P.
and Salvayre, R. (1999) Sphingomyelin-degrading pathways in human cells
role in cell signalling. Chem. Phys. Lipids. 102, 167–178.
 Stoffel, W. (1999) Functional analysis of acid and neutral sphingomyelinases
in vitro and in vivo. Chem. Phys. Lipids 102, 107–121.
 Marchesini, N. and Hannun, Y.A. (2004) Acid and neutral sphingomyelinases:
roles and mechanisms of regulation. Biochem. Cell Biol. 82, 27–44.
 Schneider, P.B. and Kennedy, E.P. (1967) Sphingomyelinase in normal human
spleens and in spleens from subjects with Niemann–Pick disease. J. Lipid Res.
 Yamanaka, T. and Suzuki, K. (1982) Acid sphingomyelinase of human brain:
purification to homogeneity. J. Neurochem. 38, 1753–1764.
 Jones,C.S., Shankaran,P. and
chromatography. Biochem. J. 195, 373–382.
 Quintern, L.E., Weitz, G., Nehrkorn, H., Tager, J.M., Schram, A.W. and Sandhoff,
K. (1987) Acid sphingomyelinase from human urine: purification and
characterization. Biochim. Biophys. Acta 922, 323–336.
 Kurth, J. and Stoffel, W. (1991) Human placental sphingomyelinase.
Purification to homogeneity, antigenic properties and partial amino-acid
sequences of the enzyme. Biol. Chem. Hoppe-Seyler 372, 215–223.
 Fowler, S. (1969) Lysosomal localization of sphingomyelinase in rat liver.
Biochim. Biophys. Acta 191, 481–484.
 Schuchman, E.H., Levran, O., Pereira, L.V. and Desnick, R.J. (1992) Structural
organization and complete nucleotide sequence of the gene encoding human
acid sphingomyelinase (SMPD1). Genomics 12, 197–205.
 Quintern, L.E., Schuchman, E.H., Levran, O., Suchi, M., Ferlinz, K., Reinke, H.,
Sandhoff, K. and Desnick, R.J. (1989) Isolation of cDNA clones encoding human
acid sphingomyelinase: occurrence of alternatively processed transcripts.
EMBO J. 8, 2469–2473.
 Pittis, M.G., Ricci, V., Guerci, V.I., Marçais, C., Ciana, G., Dardis, A., Gerin, F.,
Stroppiano, M., Vanier, M.T., Filocamo, M. and Bembi, B. (2004) Acid
sphingomyelinase: identification of nine novel mutations among Italian
Niemann Pick type B patients and characterization of in vivo functional in-
frame start codon. Hum. Mutat. 24, 186–187.
 Lansmann, S., Ferlinz, K., Hurwitz, R., Bartelsen, O., Glombitza, G. and
Sandhoff, K. (1996) Purification of acid sphingomyelinase from human
placenta: characterization and N-terminal sequence. FEBS Lett. 399, 227–
 Ferlinz, K., Hurwitz, R., Vielhaber, G., Suzuki, K. and Sandhoff, K. (1994)
Occurrence of two molecular forms of human acid sphingomyelinase.
Biochem. J. 301, 855–862.
 Ferlinz, K., Hurwitz, R., Moczall, H., Lansmann, S., Schuchman, E.H. and
Sandhoff, K. (1997) Functional characterization of the N-glycosylation sites of
human acid sphingomyelinase by site-directed mutagenesis. Eur. J. Biochem.
 Hurwitz, R., Ferlinz, K., Vielhaber, G., Moczall, H. and Sandhoff, K. (1994)
Processing of human acid sphingomyelinase in normal and I-cell fibroblasts. J.
Biol. Chem. 269, 5440–5445.
 Lansmann, S., Schuette, C.G., Bartelsen, O., Hoernschemeyer, J., Linke, T.,
Weisgerber, J. and Sandhoff, K. (2003) Human acid sphingomyelinase. Eur. J.
Biochem. 270, 1076–1088.
 Qiu, H., Edmunds, T., Baker-Malcolm, J., Karey, K.P., Estes, S., Schwarz, C.,
Hughes, H. and Van Patten, S.M. (2003) Activation of human acid
sphingomyelinase through modification or deletion of C-terminal cysteine.
Biol. Chem. 278, 32744–32752.
 Schissel, S.L., Schuchman, E.H., Williams, K.J. and Tabas, I. (1996) Zn2+-
stimulated sphingomyelinase is secreted by many cell types and is a product
of the acid sphingomyelinase gene. J. Biol. Chem. 271, 18431–18436.
 Schissel, S.L., Keesler, G.A., Schuchman, E.H., Williams, K.J. and Tabas, I. (1998)
The cellular trafficking and zinc dependence of secretory and lysosomal
sphingomyelinase, two products of the acid sphingomyelinase gene. J. Biol.
Chem. 273, 18250–18259.
 Spence, M.W., Byers, D.M., Palmer, F.B. and Cook, H.W. (1989) A new Zn2+-
stimulated sphingomyelinase in fetal bovine serum. J. Biol. Chem. 264, 5358–
 Tabas, I. (1999) Secretory sphingomyelinase. Chem. Phys. Lipids 102, 123–130.
 Réthy, L.A. (2000) Growth regulation, acid sphingomyelinase gene and
genomic imprinting: lessons from an experiment of nature. Pathol. Oncol.
Res. 6, 298–300.
 Simonaro, C.M., Park, J.H., Eliyahu, E., Shtraizent, N., McGovern, M.M. and
Schuchman, E.H. (2006) Imprinting at the SMPD1 locus: implications for acid
sphingomyelinase-deficient Niemann–Pick disease. Am. J. Hum. Genet. 78,
 Santana, P., Peña, L.A., Haimovitz-Friedman, A., Martin, S., Green, D.,
McLoughlin, M., Cordon-Cardo, C., Schuchman, E.H., Fuks, Z. and Kolesnick,
R. (1996) Acid sphingomyelinase-deficient human lymphoblasts and mice are
defective in radiation-induced apoptosis. Cell 86, 189–199.
 Lin, T., Genestier, L., Pinkoski, M.J., Castro, A., Nicholas, S., Mogil, R., Paris, F.,
Fuks, Z., Schuchman, E.H., Kolesnick, R.N. and Green, D.R. (2000) Role of acidic
E.H. Schuchman/FEBS Letters 584 (2010) 1895–1900