Lysosomes in Health and Disease
HSP70 and lysosomal storage disorders: novel
therapeutic opportunities
Nikolaj H.T. Petersen and Thomas Kirkegaard1
Danish Cancer Society, Strandboulevarden 49, 2100 Copenhagen, Denmark
Abstract
Lysosomes, with their arsenal of catabolic enzymes and crucial metabolic housekeeping functions are
experiencing a revived research interest after having lived a rather quiet life for the last few decades. With
the discovery of the interaction of the lysosomes with another ancient component of cellular homoeostasis,
the molecular chaperone HSP70 (heat-shock protein 70), the stage seems set for further discoveries
of the mechanisms regulating cellular and physiological stress responses to otherwise detrimental
challenges.
Introduction
HSPs (heat-shock proteins) are the archetypal molecular
chaperones whose main function is to prevent proteins from
misfolding, thus serving a fundamental cytoprotective role.
The HSPs are divided into subfamilies according to their
molecular masses, with the 70 kDa family being the most
prominent and evolutionarily conserved [1]. In this family,
HSPA1A/HSP70-1, commonly referred to as simply HSP70,
is the primary stress-inducible member and one of the major
cytoprotective agents in the cell.
Lysosomes are acidic organelles that receive membrane
traffic input from the biosynthetic, endocytic and autophagic
pathways. They contain numerous acid hydrolases capable
of digesting all of the major macromolecules of the cell
to breakdown products available for metabolic reutilization
[2,3]. Being the primary catabolic organelle of the cell,
lysosomes are also at the centre of a series of debilitating
metabolic genetic disorders commonly referred to as LSDs
(lysosomal storage diseases). These diseases are very rare,
a testament to the crucial role of the respective affected
enzymes in maintaining cellular function, but, for the
majority of the LSDs, treatment is non-existent. As the name
implies, the LSDs are characterized by an accumulation of
substrates in the lysosomes that compromise the function
and integrity of the organelle.
Importantly, previous studies have established HSP70 as a
specific and central regulator of lysosomal stability in cancer
[4], and ectopic expression of HSP70 in transformed cells
can reduce LMP (lysosomal membrane permeabilization),
which is a major factor in many cell death programmes
[4,5]. Despite this intriguing role of LMP and HSP70 in
Key words: acid sphingomyelinase, heat-shock protein 70 (HSP70), lysosomal storage disease
(LSD), lysosome, Niemann–Pick disease.
Abbreviations used: ASM, acid sphingomyelinase; BMP, bis(monoacylglycero)phosphate;
HSC70, heat-shock cognate 70; HSP, heat-shock protein; ILV, intraluminal vesicle; LMP, lysosomal
membrane permeabilization; LSD, lysosomal storage disease; MEF, mouse embryonic fibroblast;
M6PR, mannose 6-phosphate receptor; PBD, peptide-binding domain; rHSP70, recombinant
HSP70; SM, sphingomyelin.
1
To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2010) 38, 1479–1483; doi:10.1042/BST0381479
the regulation of cell survival, very little is known about the
mechanisms regulating lysosomal stability and the effect of
HSP70 in the lysosomes. Discovering and studying factors
involved in lysosomal stability and integrity is therefore of
crucial importance, and we set out to address this further by
investigating how HSP70 could bind lysosomal membranes.
Binding of HSP70 to a lysosome-specific
lipid stabilizes lysosomes
It is well characterized that HSP70 can be present on plasma
membranes of tumour cells, as well as in the endolysosomal
system [4,6] and that HSP70 can be released to the
bloodstream during different stress-inducing events, the most
typical being fever, trauma and strenuous exercise, although
psychological stress has also been described to trigger release
of HSP70 (reviewed thoroughly by Whitham and Fortes
[7]). In addition, the presence of HSP70 species inside the
endolysosomal compartment has also been described for
another member of the HSP70 family, the constitutively
expressed HSC70 (heat-shock cognate 70). The function of
HSC70 at this location has indeed given name to the process
known as chaperone-mediated autophagy [8].
The molecular basis for the association of HSP70
with plasma and endolysosomal membranes has, however,
remained unresolved.
Our new data show that HSP70 can be efficiently endocytosed and localized to the lysosomes [9]. This is in accordance
with data showing that extracellular HSP70 can bind to a
number of receptors on different leucocyte subpopulations.
The receptors involved in HSP70 recognition mainly include
PRRs (pattern-recognition receptors) and consist of a variety
of receptors from different receptor families such as the
TLRs (Toll-like receptors), scavenger receptors and c-type
lectins [10]. Once in the lysosomes, we found that HSP70
interacts directly with the intraluminal membranes of the
organelle [9]. These numerous intraluminal membranes are
one of the main characteristics of lysosomes and are derived
C The
C 2010 Biochemical Society
Authors Journal compilation 1479
1480
Biochemical Society Transactions (2010) Volume 38, part 6
from the ILVs (intraluminal vesicles) of late endosomes from
which the lysosomes have matured [2]. The intraluminal
membranes are characterized by a high concentration of
BMP [bis(monoacylglycero)phosphate], a lysosome-specific
anionic lipid [11,12] which is also essential in the formation
of the ILVs [13,14].
We have shown that HSP70, but not the closely related
HSP70–2 and HSC70, modulates lysosomal stability through
direct binding to BMP [9]. One of the defining properties of
BMP is its negative charge and, at low pH (4.5), the ATPase
domain of HSP70 is predominantly positively charged. This
presumably contributes to HSP70 interaction with BMP
in both large unilamellar vesicles and lipid monolayers
under acidic conditions [9]. Although HSP70 has been
shown previously to have affinity for other negatively
charged lipids [15,16], this is the first time that this has
been demonstrated unequivocally in a biologically relevant
setting.
Our working model is that HSP70 interacts with BMP via
an electrostatically positively charged wedge-like subdomain
at the bottom of the ATPase cleft [9] (Figure 1). This is on
the basis of the following: (i) the pH-dependent interaction
between HSP70 and BMP; (ii) the PBD (peptide-binding
domain) of HSP70 being only capable of much weaker
interactions with BMP; (iii) the conservative mutation of
Trp90 to phenylalanine dramatically reducing the affinity
of HSP70 to BMP; (iv) the BMP-binding properties of the
ATPase domain; (v) the different isoelectric points of the
PBD and ATPase domains of HSP70, and (vi) the molecular
modelling of surface electrostatic potential of HSP70.
It has been proposed that HSP70 contains specific binding
sites for the hydrophilic and hydrophobic parts of acidic
glycolipids both in the ATPase as well as in the PBD
[15]. Although this model might be applicable for HSP70
binding to acidic glycolipids, it does not fit with our data on
the interaction between HSP70 and BMP [9]. However, an
intermediate of the two models could explain the interaction
of HSP70 with a more common anionic lipid motif. We
propose that, in such a model, the positive surface charge of
the ATPase domain of HSP70 could facilitate electrostatic
interactions, and particular residues, such as Trp90 , might
be involved in determining specificity of binding of anionic
lipid-binding partners such as BMP. Interestingly, this model
can accommodate a view of HSP70 as a more general regulator
of lipid homoeostasis in the cell. In support of this are data
demonstrating that the lipid membranes of cells might serve as
the primary sensors of stress such as fever and oxidative stress
and hence as the initial inducers of the stress response [17,18].
In the face of stress, the lipid membranes of the cell would
be crucial compartments to maintain, or indeed modify, in
order to have a proper cellular response to the challenge. The
binding of HSP70 to lipids such as BMP and the following
increased stability of lysosomal membranes and perhaps
other cellular lipid events could thus represent a part of a
general cellular stress response. In the case of cancer, such
a response might have been hijacked to serve the cancer’s
own end, but also from a broader evolutionary perspective,
C The
C 2010 Biochemical Society
Authors Journal compilation Figure 1 Molecular modelling
(A) Basic properties of the full-length HSP70 protein (HspA1A, accession
number NP_005336) and its two domains as calculated via PROTPARAM
from the Expert Protein Analysis System (EXPaSy) proteomics server
(http://expasy.org/) of the Swiss Institute of Bioinformatics. aa, amino
acids; Mw, molecular mass. (B) Molecular surface model of the domains
of HSP70 [left: ATPase domain left (including Trp90 ); right: PBD]. The
position of Trp90 is indicated. Note the positively charged part of the
bottom of the ATPase domain and the position of Trp90 . Molecular
modelling of human Hsp70 was carried out with software available
from the EXPaSy proteomics server and DeepView-Swiss PDB Viewer
on the basis of the crystal structures of the ATPase domain (PDB code
1S3X) and the PBD (PDB code 7HSC) domains. Surface models were
on the basis of coulomb interaction at pH 7.0, using a solvent dielectric
constant of 80 (water).
a co-ordinated protein–lipid response in the face of cellular
stress would make good sense.
Our data showing that HSP70 exclusively, and not HSC70
and HSP70-2, are capable of directly protecting lysosomal
membranes argue for the notion that a potential lipid
stress response might be specifically regulated by the major
stress-inducible HSP70 itself and not other HSP70 species.
However, further investigations are needed to establish
precisely which molecular chaperones, and indeed other
stress-induced proteins, contribute to the protection of the
lysosomes.
Lysosomes in Health and Disease
ASM (acid sphingomyelinase) is a key
component in HSP70–BMP-mediated
lysosomal stabilization
Interestingly, in addition to its structural role in internal
lysosomal membranes, BMP is an important binding
site for enzymes and cofactors involved in lysosomal
catabolism of sphingolipids [11,12]. As such, it serves as a
stimulatory cofactor for enzymatic hydrolysis of not only
SM (sphingomyelin) via ASM, but of most membranebound sphingolipids, as it also functions as a cofactor for
SAPs (sphingolipid activator proteins)/saposins A–D and
ganglioside GM2 activator protein [19,20].
Sphingolipids form a class of lipids that, together with
glycerophospholipids and cholesterol, make up the lipids
of all eukaryotic membranes [21]. There are two main
types of complex sphingolipids: the structurally diverse
glycosphingolipids in which the backbone ceramide is bound
to a wide variety of different carbohydrates [22], and SM,
which contains a phosphocholine headgroup [23]. De novo
synthesis of the sphingolipid backbone takes place in the ER
(endoplasmic reticulum), whereas the downstream formation
of the more complex sphingolipids continues in the Golgi
apparatus [24]. Catabolism of sphingolipids occurs in the
lysosome and ultimately yields sphingosine, which can be
reused to form new complex sphingolipids via the ‘salvage
pathway’ [25]. The importance of a functional lysosomal
sphingolipid catabolism can be easily appreciated by the fact
that clinical diseases are apparent in the case of dysfunction
of any of the lysosomal sphingolipid-catabolizing enzymes.
This gives rise to relatively rare, but severe, diseases such
as Tay–Sachs, Sandhoff, Farber, Fabry, Gaucher, Krabbe
and Niemann–Pick diseases, the so-called sphingolipidoses,
where non-degradable lipids accumulate inside cells and give
rise to a signature cellular morphology characterized by the
vast accumulation of lysosomes [9,26] (Figure 2).
In this context, one of the best studied enzymes is ASM,
which hydrolyses SM to ceramide, and dysfunction of ASM
leads to the aforementioned detrimental lysosomal storage
diseases Niemann–Pick disease Type A and B. ASM activity
depends on its direct binding to BMP through its saposin
domain [27], and, when this interaction is disrupted, ASM
is allegedly proteolytically degraded by lysosomal proteases
[28].
In order to look deeper into the biological role of
the HSP70–BMP interaction and its possible therapeutic
perspectives, we thus decided to look at the effect of rHSP70
(recombinant HSP70) on the binding between ASM and BMP.
Surprisingly, HSP70 is capable of modulating the binding of
ASM to BMP-containing liposomes at pH 4.5, depending on
the concentration of HSP70. Low concentrations (3–150 nM)
of pre-bound HSP70 facilitate the interaction of ASM with
BMP–HSP70 liposomes, whereas higher concentrations of
HSP70 (300–1500 nM) compete with ASM for the binding
to BMP [9]. A direct translation of such an in vitro result is,
of course, challenging, given that the specific intralysosomal
concentration of HSP70 in an in vivo setting is impossible
Figure 2 Lysosomal morphology in Niemann–Pick Type A disease
and its correction by rHSP70
(A) Primary fibroblasts from a healthy individual (left-hand panel) and
a patient suffering from Niemann–Pick Type A disease (right-hand
panel). Cells were labelled with Acridine Orange, a metachromatic weak
base that accumulates in the acidic lysosomes (red staining). Note
the vast increase in lysosomes occupying almost the entire cytosol in
the cells from the Niemann–Pick Type A disease patient. (B) Primary
fibroblasts from an Niemann–Pick Type A disease patient stained with
the lysosomal marker LysoTrackerTM Red (red fluorescence) either left
untreated (left-hand panel) or treated with rHSP70 (green fluorescence)
(middle and right-hand panel). The green spectrum was removed from
the right-most panel to facilitate the visualization of the red. Notice
the remarkable reversal of lysosomal morphology in cells treated with
rHSP70. Scale bars, 50 μm.
to determine. However, the HSP70-mediated increase in
ASM–BMP binding is reflected by increased ASM activity
upon treatment of MEFs (mouse embryonic fibroblasts) with
HSP70, as well as in MEFs transgenic for human HSP70,
clearly demonstrating that, in vivo, HSP70 facilitates ASM
binding to BMP [9].
Remarkably, both pharmacological and genetic inhibition
of ASM destabilize lysosomal membranes, suggesting that
ASM activation is likely to play a crucial role in the HSP70mediated stabilization of lysosomes [9].
HSP70 and sphingolipid catabolism:
mechanistic insight into lysosomal stability
In addition to its presence at the internal membranes of the
lysosomes, ASM can also be exported to the cell surface [27].
Here, ASM can mediate assembly of signalling complexes in
ceramide-rich membrane domains, which accounts for many
C The
C 2010 Biochemical Society
Authors Journal compilation 1481
1482
Biochemical Society Transactions (2010) Volume 38, part 6
of its reported pro-death functions [29]. The lack of BMP
on the plasma membrane and the clear absence of HSP70 on
the plasma membrane in our studies [9], however, suggests
that the HSP70-mediated rise in ASM activity is a lysosomespecific effect. A central question regarding the protective role
of HSP70 on lysosomes thus remains: how can the presence
of a molecular chaperone affect the stability of a whole
organelle? On the basis of our data that HSP70 increases ASM
activity, we suggest that a change in the lipid composition of
inner lysosomal membranes has a direct and potent influence
on the stability of the entire lysosome. Whether this is due
to a direct effect on the outer lysosomal membrane, or by
other indirect means, is presently unknown. One hypothesis
could be that, since generation of ceramide greatly alters the
properties of membranes [30], an ASM-dependent increase
in lysosomal ceramide content could in itself have a positive
impact on the stability of the outer membrane. Alternatively,
lower levels of the ASM substrate SM might be the crucial
factor.
Sphingolipid composition of ILVs in late endosomes
is decisive for whether they end up as exosomes or as
internal membranes in lysosomes [31]. Thus it is important
to remember that the lysosomes are far from being static
organelles, but rather a part of a highly dynamic endocytic
system of membranes with continuous membrane fusions and
budding [2,3]. HSP70 and ASM could therefore influence the
properties of a whole set of dynamic endocytic membranes
in a way that ultimately has a positive effect on lysosomal
integrity.
A possible novel therapy for LSDs?
Finally, and perhaps most importantly, we found that the
dramatic increase in lysosomal volume and decrease in
lysosomal stability associated with reduced ASM activity
in cells from patients with Niemann–Pick disease can
be effectively corrected by treatment with rHSP70 [9]
(Figure 2B). Treatment of primary fibroblasts from patients
suffering from both type A and B Niemann–Pick disease with
rHSP70 led to an increase in the residual activity of ASM,
reduction in SM burden and, most importantly, correction of
the pathological lysosomal morphology.
Together with previous observations that exogenously
added HSP70 could have therapeutic potential towards
neuronal damage [32,33], this opens up the possibility of
investigating the potential beneficial effects of rHSP70 in the
treatment of Niemann–Pick disease, as well as other LSDs. Of
particular note, it cannot be ruled out that HSP70 influences
additional enzymes, since multiple lysosomal sphingolipidand phospholipid-degrading enzymes require anionic lipids,
particularly BMP [11,19,34,35], and HSP70 binds specifically
to BMP [9]. On the other hand, ASM is special in the sense
that it binds directly to BMP, whereas most other lipases
do so via essential co-factors such as GM2 activator protein
and saposins [11,12]. It is thus not yet known whether
HSP70 has a positive effect on binding between BMP and the
various activator proteins. Additionally, the ceramide species
C The
C 2010 Biochemical Society
Authors Journal compilation generated by different enzymes such as ASM and GBA1 (acid
β-glucosidase 1), are not necessarily identical, and might have
different effects on lysosomal stability.
Moreover, rHSP70 endocytosis is presumably not dependent on M6PR (mannose 6-phosphate receptor)-mediated
uptake and is capable of binding to a number of receptors
on different leucocyte populations, including macrophages
[7,10]. This aspect of HSP70 biology could be of clinical
importance, as M6PR-mediated uptake is defective in ASMdeficient macrophages, one of the hallmark affected cell
types of Niemann–Pick disease [36–38].
Funding
N.H.T.P. is supported by a grant from the Danish Cancer Society. T.K.
is supported by a pre-seed grant from the Novo Nordisk Foundation.
References
1 Daugaard, M., Rohde, M. and Jaattela, M. (2007) The heat shock protein
70 family: highly homologous proteins with overlapping and distinct
functions. FEBS Lett. 581, 3702–3710
2 Saftig, P. and Klumperman, J. (2009) Lysosome biogenesis and
lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol.
Cell Biol. 10, 623–635
3 Luzio, J.P., Pryor, P.R. and Bright, N.A. (2007) Lysosomes: fusion and
function. Nat. Rev. Mol. Cell Biol. 8, 622–632
4 Nylandsted, J., Gyrd-Hansen, M., Danielewicz, A., Fehrenbacher, N.,
Lademann, U., Hoyer-Hansen, M., Weber, E., Multhoff, G., Rohde, M. and
Jaattela, M. (2004) Heat shock protein 70 promotes cell survival by
inhibiting lysosomal membrane permeabilization. J. Exp. Med. 200,
425–435
5 Kirkegaard, T. and Jaattela, M. (2009) Lysosomal involvement in cell
death and cancer. Biochim. Biophys. Acta 1793, 746–754
6 Multhoff, G., Botzler, C., Jennen, L., Schmidt, J., Ellwart, J. and Issels, R.
(1997) Heat shock protein 72 on tumor cells: a recognition structure for
natural killer cells. J. Immunol. 158, 4341–4350
7 Whitham, M. and Fortes, M.B. (2008) Heat shock protein 72: release and
biological significance during exercise. Front. Biosci. 13, 1328–1339
8 Chiang, H.L., Terlecky, S.R., Plant, C.P. and Dice, J.F. (1989) A role for a
70-kilodalton heat shock protein in lysosomal degradation of intracellular
proteins. Science 246, 382–385
9 Kirkegaard, T., Roth, A.G., Petersen, N.H., Mahalka, A.K., Olsen, O.D.,
Moilanen, I., Zylicz, A., Knudsen, J., Sandhoff, K., Arenz, C. et al. (2010)
HSP70 stabilizes lysosomes and reverts Niemann–Pick diseaseassociated lysosomal pathology. Nature 463, 549–553
10 Calderwood, S.K., Theriault, J., Gray, P.J. and Gong, J. (2007) Cell surface
receptors for molecular chaperones. Methods 43, 199–206
11 Kolter, T. and Sandhoff, K. (2010) Lysosomal degradation of membrane
lipids. FEBS Lett. 584, 1700–1712
12 Schulze, H., Kolter, T. and Sandhoff, K. (2009) Principles of lysosomal
membrane degradation: cellular topology and biochemistry of lysosomal
lipid degradation. Biochim. Biophys. Acta 1793, 674–683
13 Matsuo, H., Chevallier, J., Mayran, N., Le Blanc, I., Ferguson, C., Fauré, J.,
Blanc, N.S., Matile, S., Dubochet, J., Sadoul, R. et al. (2004) Role of LBPA
and Alix in multivesicular liposome formation and endosome
organization. Science 303, 531–534
14 Kobayashi, T., Stang, E., Fang, K.S., de Moerloose, P., Parton, R.G. and
Gruenberg, J. (1998) A lipid associated with the antiphospholipid
syndrome regulates endosome structure and function. Nature 392,
193–197
15 Harada, Y., Sato, C. and Kitajima, K. (2007) Complex formation of 70-kDa
heat shock protein with acidic glycolipids and phospholipids. Biochem.
Biophys. Res. Commun. 353, 655–660
16 Arispe, N., Doh, M., Simakova, O., Kurganov, B. and De Maio, A. (2004)
HSC70 and HSP70 interact with phosphatidylserine on the surface of
PC12 cells resulting in a decrease of viability. FASEB J. 18, 1636–1645
Lysosomes in Health and Disease
17 Vigh, L., Nakamoto, H., Landry, J., Gomez-Munoz, A., Harwood, J.L. and
Horvath, I. (2007) Membrane regulation of the stress response from
prokaryotic models to mammalian cells. Ann. N.Y. Acad. Sci. 1113, 40–51
18 Balogh, G., Horvath, I., Nagy, E., Hoyk, Z., Benko, S., Bensaude, O. and
Vigh, L. (2005) The hyperfluidization of mammalian cell membranes acts
as a signal to initiate the heat shock protein response. FEBS J. 272,
6077–6086
19 Ferlinz, K., Linke, T., Bartelsen, O., Weiler, M. and Sandhoff, K. (1999)
Stimulation of lysosomal sphingomyelin degradation by sphingolipid
activator proteins. Chem. Phys. Lipids 102, 35–43
20 Kolter, T. and Sandhoff, K. (2005) Principles of lysosomal membrane
digestion: stimulation of sphingolipid degradation by sphingolipid
activator proteins and anionic lysosomal lipids. Annu. Rev. Cell Dev. Biol.
21, 81–103
21 van, M.G., Voelker, D.R. and Feigenson, G.W. (2008) Membrane lipids:
where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9,
112–124
22 Merrill, Jr, A.H., Wang, M.D., Park, M. and Sullards, M.C. (2007)
(Glyco)sphingolipidology: an amazing challenge and opportunity for
systems biology. Trends Biochem. Sci. 32, 457–468
23 Hannun, Y.A. and Obeid, L.M. (2008) Principles of bioactive lipid
signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9, 139–150
24 Futerman, A.H. and Riezman, H. (2005) The ins and outs of sphingolipid
synthesis. Trends Cell Biol. 15, 312–318
25 Kitatani, K., Idkowiak-Baldys, J. and Hannun, Y.A. (2008) The sphingolipid
salvage pathway in ceramide metabolism and signaling. Cell. Signalling
20, 1010–1018
26 Kolter, T. and Sandhoff, K. (2006) Sphingolipid metabolism diseases.
Biochim. Biophys. Acta 1758, 2057–2079
27 Jenkins, R.W., Canals, D. and Hannun, Y.A. (2009) Roles and regulation of
secretory and lysosomal acid sphingomyelinase. Cell. Signalling 21,
836–846
28 Kolzer, M., Werth, N. and Sandhoff, K. (2004) Interactions of acid
sphingomyelinase and lipid bilayers in the presence of the tricyclic
antidepressant desipramine. FEBS Lett. 559, 96–98
29 Carpinteiro, A., Dumitru, C., Schenck, M. and Gulbins, E. (2008)
Ceramide-induced cell death in malignant cells. Cancer Lett. 264, 1–10
30 Stancevic, B. and Kolesnick, R. (2010) Ceramide-rich platforms in
transmembrane signaling. FEBS Lett. 584, 1728–1740
31 Trajkovic, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F.,
Schwille, P., Brugger, B. and Simons, M. (2008) Ceramide triggers
budding of exosome vesicles into multivesicular endosomes. Science
319, 1244–1247
32 Robinson, M.B., Tidwell, J.L., Gould, T., Taylor, A.R., Newbern, J.M., Graves,
J., Tytell, M. and Milligan, C.E. (2005) Extracellular heat shock protein 70:
a critical component for motoneuron survival. J. Neurosci. 25, 9735–9745
33 Tidwell, J.L., Houenou, L.J. and Tytell, M. (2004) Administration of HSP70
in vivo inhibits motor and sensory neuron degeneration. Cell Stress
Chaperones 9, 88–98
34 Abe, A. and Shayman, J.A. (2009) The role of negatively charged lipids in
lysosomal phospholipase A2 function. J. Lipid Res. 50, 2027–2035
35 Wilkening, G., Linke, T., Uhlhorn-Dierks, G. and Sandhoff, K. (2000)
Degradation of membrane-bound ganglioside GM1: stimulation by
bis(monoacylglycero)phosphate and the activator proteins SAP-B and
GM2-AP. J. Biol. Chem. 275, 35814–35819
36 Dhami, R. and Schuchman, E.H. (2004) Mannose 6-phosphate
receptor-mediated uptake is defective in acid sphingomyelinasedeficient macrophages: implications for Niemann–Pick disease enzyme
replacement therapy. J. Biol. Chem. 279, 1526–1532
37 Miranda, S.R., He, X., Simonaro, C.M., Gatt, S., Dagan, A., Desnick, R.J. and
Schuchman, E.H. (2000) Infusion of recombinant human acid
sphingomyelinase into Niemann–Pick disease mice leads to visceral, but
not neurological, correction of the pathophysiology. FASEB J. 14,
1988–1995
38 Schuchman, E.H. (2007) The pathogenesis and treatment of acid
sphingomyelinase-deficient Niemann–Pick disease. J. Inherit. Metab. Dis.
30, 654–663
Received 13 May 2010
doi:10.1042/BST0381479
C The
C 2010 Biochemical Society
Authors Journal compilation 1483