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PHYSIOLOGY 25: 102–115, 2010; doi:10.1152/physiol.00041.2009
Lysosomal Storage Disease: Revealing
Lysosomal Function and Physiology
The discovery over five decades ago of the lysosome, as a degradative
organelle and its dysfunction in lysosomal storage disorder patients, was both
insightful and simple in concept. Here, we review some of the history and
Emma J. Parkinson-Lawrence,
Tetyana Shandala, Mark Prodoehl,
Revecca Plew, Glenn N. Borlace, and
Doug A. Brooks
Cell Biology of Disease Research Group, Sansom Institute for
Health Research, Division of Health Science, University of South
Australia, Adelaide; and Lysosomal Diseases Research Unit,
Women’s and Children’s Hospital, South Australian Pathology
Services, Adelaide, Australia
[email protected]
pathophysiology of lysosomal storage disorders to show how they have impacted on our knowledge of lysosomal biology. Although a significant amount
of information has been accrued on the molecular genetics and biochemistry
of lysosomal storage disorders, we still do not fully understand the mechanisaccumulation of undegraded substrate(s) can disrupt other lysosomal degradation processes, vesicular traffic, and lysosomal biogenesis to evoke the
diverse pathophysiology that is evident in this complex set of disorders.
The lysosome was first described by De Duve et al. in
1955 and is an acidic organelle containing an array of
lysosomal hydrolases (31). Macromolecules are delivered toward lysosomes for degradation via either
endocytic pathways from the extracellular environment or by routes from the cytosol (35, 68, 101).
Specialist endosomes and lysosomes have many important functions within cells, including antigen
presentation, innate immunity, autophagy, signal
transduction, cell division, and neurotransmission.
Each component of the endosome-lysosome system
is a potential target for dysfunction leading to a diseased state (FIGURE 1).
Lysosomal storage disorders comprise a group of
more than 50 different genetic diseases (124).
These disorders mostly involve the dysfunction of
lysosomal hydrolases, which result in impaired
substrate degradation. However, proteins involved
in vesicular traffic and the biogenesis of lysosomes
have also been shown to cause storage disorder
phenotypes. Any disruption of lysosomal function
can lead to the accumulation of undegraded substrate(s) in endosomes and lysosomes, eventually
compromising cellular function (55).
Although lysosomal proteins are ubiquitously
distributed, the accumulation of undegraded substrate(s) in lysosomal storage disorder patients is
normally restricted to those cells, tissues, and organs in which substrate turnover is high. The accumulation of the primary storage material can
cause a chain of secondary disruptions to other
biochemical and cellular functions, which leads to
the severe pathology in lysosomal storage disorders. This review will discuss the pathophysiology
of selected lysosomal storage disorders and how
these diseases have informed our knowledge on
102
lysosomal cell biology and function (FIGURE 2). We
have discussed the following disorders: Pompe disease because of its pivotal role in defining the
concept of enzyme deficiency and lysosomal storage disorder biology; the mucopolysaccharidoses
and the lipidoses, which are themselves major
groups of disorders that provide early clinical descriptions, reveal important biological pathways,
and highlight interconnecting pathological cascades; I-cell and multiple sulphatase deficiencies,
which are representative of protein targeting/processing defects; and the albinism disorders, which
reveal a new class of vesicular trafficking, lysosomal-related disorders.
Pompe Disease
In 1932, Pompe made the critical observation of
extensive glycogen accumulation, within membrane-bound vesicles in the heart muscle, of a
7-mo-old patient who had died from cardiac complications (96). The metabolic basis of Pompe disease was determined later by delineating the
glycogen metabolism pathway (27) and defining a
new cellular organelle, the lysosome (31). Based on
these findings, Hers and coworkers deduced the
link between the deposition of glycogen in Pompe
patients and the inherited deficiency of the lysosomal enzyme ␣-D-glucosidase (50). The involvement of the lysosome in glycogen degradation gave
rise to the concept that other lysosomal storage
disorders could also be explained by specific enzyme deficiencies.
Pompe patients present within a spectrum of clinical phenotypes that can be defined by the age of
onset, rate of disease progression, and degree of
1548-9213/10 $8.00 ©2010 Int. Union Physiol. Sci./Am. Physiol. Soc.
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tic link between the storage material and disease pathogenesis. However, the
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cardiac and/or skeletal muscle involvement (Table 1)
(52). In the infantile form of Pompe disease, patients present with rapidly progressive cardiac and
skeletal myopathy (52). Death usually occurs in the
first year of life, primarily due to cardiorespiratory
failure. Pathophysiology studies have shown the
progressive enlargement of glycogen storage vesicles, with evidence of autophagic storage vacuoles
(FIGURE 3D) in type II, but not type I, muscle fibers
(39, 40, 100). In addition, acidification defects in
populations of endosomes and lysosomes and decreased vesicular mobility have been reported in
Pompe cells (40), suggesting a secondary defect in
vesicular traffic.
Enzyme replacement therapy has been developed for Pompe patients and utilizes the extracellular uptake of functional enzyme by cell
surface mannose-6-phosphate receptors. This
therapy can clear glycogen in cardiac muscle but
has been less effective in skeletal muscle, particularly for the autophagic glycogen in type II fibers (39, 98). This failure of enzyme replacement
therapy to clear glycogen from skeletal muscle
may be due to the inability of endocytozed enzyme to reach storage compartments either due
to the limited number of mannose-6-phosphate
receptors on these muscle cells or due to disrupted vesicular traffic in type II fibers. The fact
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FIGURE 1. Stylized cell showing the functions that can be disrupted in lysosomal storage disorders
Pompe disease involves a lysosomal hydrolase defect that results in the inability to degrade autophagocytozed vesicular glycogen. The mucopolysaccharidoses
(MPS) involve different defects in either a processing enzyme, glycosidase, or sulphatase and impact on glycosaminoglycan degradation within the
lysosome. The sphingolipidoses (lipidoses) involve different hydrolase defects that alter the lysosomal catabolism of lipids. I-cell disease involves a
Golgi processing enzyme defect, altering the traffic of soluble lysosomal hydrolsases to the lysosome and causing the secretion of these enzymes.
Multiple sulphatase deficiency (MSD) prevents the active site processing of sulphatases in the endoplasmic reticulum, generating catalytically inactive
sulphatase proteins. The hereditary albinism syndromes Chediak-Higashi (CHS), Hermansky-Pudlak (HPS), and Griscelli (GS) each impact on different
aspects of vesicular traffic, altering the biogenesis of lysosomal-related organelles (LRO). Because of the dynamic interrelationship of the endosome lysosome system, these primary defects can have a secondary impact on other lysosomal function.
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The Mucopolysaccharidoses
Hurler (␣-L-iduronidase deficiency) and Hunter
(iduronate-2-sulphatase deficiency) syndromes were
the first of the mucopolysaccharidoses to be described (FIGURE 2) (60). However, the term mucopolysaccharidoses was not suggested until 1952,
after the identification of excessive amounts of glycosaminoglycan in samples from patients with
Hurler syndrome (18, 36). Observations of different
relative amounts of heparan, dermatan, keratan,
and chondroitin sulphates in patient urines confirmed that there were multiple syndromes (46, 77,
81, 103).
The mucopolysaccharidoses were originally thought
to result from the overproduction of glycosaminoglycans, but van Hoof and Hers proposed that these
disorders were analogous to Pompe disease and
therefore due to specific lysosomal hydrolase deficiencies. This was consistent with the detection of
enlarged lysosomes in Hurler hepatocytes (113) and
35
SO4 uptake studies in Hurler fibroblasts, demonstrating impaired glycosaminoglycan degradation
(37). The classification of the mucopolysaccharidoses (85) now recognizes 10 different diseases (types
I, II, IIIA, IIIB, IIIC, IIID, IVA, IVB, VI, and VII), each
caused by a deficiency in the activity of a specific
lysosomal hydrolase involved in the sequential
degradation of one or more glycosaminoglycans.
Patients can present within a spectrum of clinical
phenotypes and have symptoms that include somatic, skeletal, and neural dysfunction (Table 1)
(92). The studies on the metabolic basis of the
mucopolysaccharidoses have increased our knowledge of the complex degradative pathways associated with the lysosome.
Although the primary defect in the mucopolysaccharidoses leads to glycosaminoglycan storage, the secondary accumulation of gangliosides in
FIGURE 2. Timeline for discoveries on lysosomal storage disorders (LSD) and their impact on cell biology
Although some of the lipidoses and mucopolysaccharidoses (MPS) were the first of the lysosomal storage disorders to be described, much of the
initial concept for the lysosome and its dysfunction came from the studies of Pompe disease. However, the lipidoses and mucopolysaccharidoses
were crucial in initiating studies on the biology of lipids and glycosaminoglycan (GAG) degradation. The knowledge developed on enzyme dysfunction and cross correction in lysosomal storage disorders was fundamentally important in developing an understanding of endocytic processes and
the subsequent development of enzyme replacement therapy (ERT).
104
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that only type II skeletal muscle fibers display
disorganization of the intracellular microtubule
trafficking network, in areas of autophagic accumulation (40, 97, 99), is consistent with the disruption of
vesicular traffic. The combination of altered vesicular
traffic and autophagic accumulation of glycogen is
clearly central in the development of the pathophysiology in Pompe disease.
The autophagic pathway has been implicated in
the pathogenesis of other lysosomal storage disorders including multiple sulphatase deficiency, mucopolysaccharidosis IIIA, mucolipidosis IV, Batten
disease, and Niemann-Pick disease (62, 64, 66,
106). Activation of autophagy may represent a
common response mechanism by affected cells
trying to engulf and clear undegraded substrate
and nonfunctional organelles.
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Table 1. Lysosomal storage disorders: patterns of storage, pathophysiology, and implications for cell biology
Disorder
Storage Pattern
Pathophysiology
Common to Other
Disorders
Cell Biology
Pompe disease GSD II, Electron dense inclusions
AMD
Autophagic accumulation
in type II muscle fibres
Cell debris, lipofuscin,
ubiquitinated proteins
Cardiomegaly and cardiorespiratory failure
Hepatomegaly and
macroglossia
Progressive muscle
weakness
Organomegaly
Cardio-respiratory
symptoms
Autophagic vacuoles
Lysosomal glycogen
hydrolysis
Mannose-6-phosphate
targeting
Autophagy in skeletal
muscle
Dysfunctional fusion of
vesicles
Mucopolysaccharidoses Electron luscent vacuoles
MPS
Electron dense inclusions
Lamellar and zebra
bodies
Ubiquitin positive bodies
Growth restriction
Organomegaly
Dysostosis multiplex
Cardio-respiratory symptoms
Mental retardation
Organomegaly
Growth restriction
Lipid accumulation
Neurological dysfunction
(some MPS)
Hydrolase degradation
pathways
Secondary storage
Microglial activation
Gaucher disease
Glucocerebroside in
tubular bilaminar
structures
Macrophages with
“wrinkled paper”
appearance
Hepatosplenomegaly
Osteonecrosis (types 1
and 3)
Acute (type 2) and subacute
(type 3) neurodegeneration
Organomegaly
Lipid accumulation
Neurological dysfunction
(type 2)
Lipid degradation in
macrophages
Alternatively activated
macrophages
Macrophage mannose
receptor targeting
Fabry disease
Electron dense inclusions
Granular or lamellar
lipids
Zebra bodies
Renal and Cardiac
symptoms
Gastrointestinal symptoms
Angiokeratoma
Growth restriction
Cerebrovascular symptoms
Growth restriction
Cardio-respiratory
problems
Lipid accumulation
Glycosphingolipid
hydrolysis
Disruption of caveolae
function
Inflammation &
reactive oxygen
species (ROS)
signalling
Niemann-Pick disease
(Types A, B, and C)
Organomegaly
Electron dense inclusions Hepatosplenomegaly
Lamellar lipids
“Cherry-red” spot in the eye Lipid accumulation
Lipid-raft signalling
Zebra bodies
Respiratory failure,
defects
pneumonia
Respiratory Failure
Purkinje cell apoptosis
Neurological dysfunction
Neurological symptoms
Cholesterol transport
Disruption of lipid-rafts
Ceramide related
apoptosis
Phospholipid
processing
Neuronal synaptic
vesicle docking
GM2 Gangliosidoses
(Tay-Sachs, Sandhoff)
Electron dense inclusions Hepatosplenomegaly
Lamellar lipids
(Sandhoff)
Zebra bodies
Neurological symptoms
Bronchopneumonia
“Cherry-red” spot in the eye
Organomegaly
Neurological dysfunction
Lipid accumulation
Lipid-raft signalling
defects
Lysosomal sphingolipid
hydrolysis
Glial cell expansion
and inflammation
Neuronal
dendritogenesis
I-cell disease ML II, ML
III
Electron dense inclusions Severe growth restriction
Lamellar lipids
Organomegaly
Zebra bodies
Dysostosis multiplex
Cardio-respiratory symptoms
Mental retardation
Oganomegaly
Dysostosis multiplex
Lipid accumulation
Neurological dysfunction
Increased enzyme
secretion
Recognition of
mannose-6-phosphate
lysosomal targeting
the brains of affected patients (21) has been postulated to be a causal factor in neuropathology
(63). For example, the accumulation of ganglioside
(GM2) has been associated with ectopic dendritogenesis, which alters the synaptic connectivity and
plasticity of neurons (84). In addition, the secondary
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Major Clinical Symptoms
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Table 1. (continued)
Storage Pattern
Major Clinical Symptoms
Pathophysiology
Common to Other
Disorders
Cell Biology
Multiple sulphatase
deficiency MSD
Metachromatic staining
Granular and lipid
storage
Growth restriction
Organomegaly
Dysostosis multiplex
Cardio-respiratory symptoms
Mental retardation
Organomegaly
Dysostosis multiplex
Lipid accumulation
Some similarities to I-cell
disease
Neurological dysfunction
Sulphatase processing
Active site of
sulphatases
Sulphatase structure
Chediak-Higashi
syndrome CHS
Giant inclusions in
leukocytes
Platelet granule
deficiency
Altered vesicular traffic
Hypopigmentation/albinism
Lipid accumulation
of the skin, eye, and hair
Neurological dysfunction
Immune deficiency
Hemophagocytosis in organs
Hermansky-Pudlak
syndrome HPS1,
HPS2
Storage of ceroidlipofucsin in leukocytes
Accumulated surfactant
phospholipids
Platelet granule
deficiency
Giant lammelar bodies
Partial hypopigmentation
Granulomatous colitis
Pulmonary fibrosis
Immune deficiency (HPS2)
Prolonged bleeding
Neutropenia
Altered vesicular traffic
Lipid accumulation
Missorting of cargo
proteins
Altered vesicular traffic
Inflammation
Griscelli syndrome
GS
Storage of melanin
Giant melanosomes in
hair shafts
Clustering of
melanosomes in the
perinuclear region
Hypopigmentation in hair
and retinal pigment
epithelium
Neurologic symptoms (GS1)
Immune-deficiency (GS2)
Hemophagocytosis (GS2)
Hypogammaglobulinemia
Altered vesicular traffic
Lipid accumulation
Altered vesicular traffic
Reduced T-cell
cytotoxicity
Defects in lytic
granules
Inflammation
impact of storage on the lysosomal system may
modulate the recycling of the neurotransmitter
receptor AMPA, which also induces ectopic dendritogenesis (118). Ultrastructural studies on mucopolysaccharidosis brain tissue have demonstrated
extensive vacuolation in neurons and glia in different regions of the brain, with electron lucent vesicles and multivesicular structures (represented in
FIGURE 3), containing mixed granular and membranous lipid storage material (11, 29, 43, 115).
Notably, the gangliosides GM2 and GM3 are not
always present in the same vesicular structures and
do not necessarily colocalize with the primary storage material. This has raised the question of
whether ganglioside accumulation is due to the
secondary inhibition of glycosphingolipid degradation or, alternatively, reflects the general disruption to lysosomal biogenesis in these complex
pathogenic diseases (84).
The transport of neuronal growth factors is critical for neuronal survival and function, and alterations in vesicular traffic have been implicated in
mucopolysaccharidosis neuropathology (19, 114,
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Altered vesicular traffic
and vesicular fusion
Macrophage activation
Altered antigen
presentation
Inflammation
118). Impaired autophagy also appears to be involved in the brain pathogenesis observed in the
mucopolysaccharidoses (106). The presence of activated microglia, elevated levels of inflammatory
cytokines, and oxidative stress all support a substantial role for inflammation in the neuropathology associated with the mucopolysaccharidoses
(19, 48, 94). Animal models [e.g., mucopolysaccharidosis types I (26), IIIA (11, 29), IIIB (74)] are currently being used to investigate the mechanisms that
link lysosomal dysfunction and neuropathology.
Clearly, the neuropathology in the mucopolysaccharidoses involves the interplay of an array of complex
mechanisms, which reflects some of the specialist
functions that are now attributed to the lysosome.
Thus autophagocytosis, apoptosis, inflammation,
and impaired neurotransmission have all been implicated in the devastating pathology associated with
the mucopolysaccharidoses.
Critical cross-correction studies using Hunter
and Hurler fibroblasts (38) were a key step in
recognizing lysosomal enzyme secretion and uptake mechanisms (FIGURE 2) and pivotal in devel-
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Disorder
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oping enzyme replacement therapy as a treatment
for lysosomal storage disorder patients. Although
intravenous enzyme replacement therapy has
been successful for the amelioration of somatic
pathology, it has proven less effective for skeletal
pathology and had minimal impact on neuropathology. This is most likely due to the inability of
enzyme to access sites of pathology distant from
the circulation and to cross the blood-brain
barrier.
Sphingolipidoses
Gaucher disease
Phillippe Gaucher was the first to describe the clinical features and the lipid-laden macrophages that are
hallmarks of this disorder (42). Later, it was recognized that this storage material involved the accumulation of glucocerebroside (2) in lysosomal organelles
(121). In 1965, Brady and coworkers demonstrated
that Gaucher disease was caused by a defect in the
lysosomal hydrolase ␤-glucocerebrosidase (16, 95).
Although the defect in ␤-glucocerebrosidase is systemic, glucocerebroside storage is restricted mainly
to cells of the macrophage lineage. Clinically, this
results in hepatosplenomegaly, skeletal pathology,
pancytopenia, and, in variant forms of the disorder,
neuropathology (Table 1).
␤-Glucocerebrosidase acts to catabolize the degradation of glucocerebroside into glucose and
ceramide, the latter of which is a known second
messenger for activating the apoptotic cascade.
Glucocerebroside is a common intermediate in the
degradation of plasma membrane gangliosides
and globosides. These substrates are believed to be
primarily derived from the membranes of apoptotic red and white blood cells, which are normally
phagocytosed by macrophages for recycling.
Gaucher macrophages appear as enlarged cells
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Gaucher, Niemann-Pick, Tay-Sachs, and Fabry diseases were among the first lysosomal storage disorders to be described (FIGURE 2). Initially,
Gaucher and Niemann-Pick diseases were termed
xanthomatoses until Ludwig Pick proposed the
term lipidoses, based on the abnormal amounts of
lipid in patient serum samples. A shared histological feature of these disorders was the presence of
highly vacuolated cells with a foamy appearance.
Gaucher, Niemann-Pick, Tay-Sachs, and Fabry diseases are now all recognized as lipid storage disorders
and collectively referred to as the sphingolipidoses. This classification was substantiated by
the identification of the specific storage material in
these disorders, including glucocerebroside in
Gaucher disease, sphingomyelin in Niemann-Pick
disease, N-acetylgalactosaminyl-(N-acetylneuraminyl)galactosylglucosylceramide (GM2) in Tay-Sach
disease, and globotriaosylceramide in Fabry
disease (67).
Each of the sphingolipidoses is associated with a
specific lysosomal hydrolase deficiency: ␤-glucocerebrosidase in Gaucher disease, sphingomyelinase
in Niemann-Pick disease, ␤-hexosaminidase A and
B in Tay-Sachs disease, and ␣-galactosidase in
Fabry disease (67). The localization of these activities to the lysosome was an important step in
understanding the pathophysiology of the lipidoses. Moreover, similar disturbances in lipid
metabolism are evident in other lysosomal storage
disorders. For example, studies on Niemann-Pick
disease have elucidated roles for the traffic of cholesterol (and possibly other cargo) out of the lysosome/late endosome (93, 120), and cholesterol
accumulation appears to be a common feature for
many lysosomal storage disorders.
FIGURE 3. Morphology of storage compartments commonly observed in lysosomal storage disorder cells
A: floccular-granular storage. B: lipid whorls. C: zebra bodies. D: autophagic vacuoles. For example, in the mucopolysacchridoses, A is typical of the
primary storage vacuoles observed early in the disease course, whereas other storage compartments appear later in the disease process due to autophagy (D) and the secondary disruption of lipid metabolism (B and C).
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therapy in Gaucher disease reflects the high accessibility of enzyme to visceral tissues and to macrophages in the circulatory system (23).
Niemann-Pick disease
Discovery of the underlying cause of Niemann-Pick
pathology, lysosomal accumulation of cholesterol,
was greatly aided by mouse models of types A, B, C1,
and C2. Niemann-Pick disease can be caused by
three gene products (ASM, NPC1, and NPC2) acting
on two pathways: sphingomyelin hydrolysis and cholesterol transport. The complex interrelationship between the key components involved in each of these
pathways may explain the similarities in the pathological features displayed in patients with lipid storage disorders (Table 1). Sphingomyelin and its
hydrolytic byproduct ceramide are intimately associated with cholesterol, showing either affinity in the
case of sphingomyelin (45) or exclusion properties in
the case of ceramide (110). These lipids are key components for the formation and function of detergentresistant membrane microdomains or “lipid-rafts.”
Lipid-rafts are postulated to act as a platform on the
plasma membrane, recruiting molecules to coordinate and amplify signaling responses. Thus research
into the mechanism of Neimann-Pick pathology has
highlighted the role of sphingomyelin, ceramide, and
cholesterol in lipid-raft formation and function.
The loss of sphingomyelinase activity in NeimannPick disease has a significant impact at the plasma
membrane through its effect on ceramide production and lipid raft formation (54). A loss of sphingomyelinase activity may alter apoptotic signaling,
which has been associated with Purkinje cell loss in
the cerebellum and may account for some of the
neurological features in Niemann-Pick disease (78).
Moreover, sphingomyelin can accumulate at inappropriate sites in neurons of Niemann-Pick patients,
resulting in defective neuronal survival, synaptic vesicle docking, and potentially synaptic function (22).
This further highlights the link between disturbed
lipid metabolism, altered lysosomal function, and
neuropathology in the lysosomal storage disorders.
Due to the affinity of cholesterol for sphingomyelin and other lipids (GM2, GM3, sphingosine, and
the lysosome specific phospholipid LBPA), perturbations in the localization of cholesterol may alter
the distribution of other lipids. This has been
shown to cause impaired trafficking and disrupted
recovery of mannose-6-phospate receptors and
other tubulovesicular structures from late endosomes (65, 125). Interestingly, this phenotype has
been modulated in vitro by over expression of the
small GTPase Rab9, which is part of the vesicular
trafficking machinery, and this reduced the
amount of cholesterol accumulation (25) and lipid
storage (91). The loss of NPC1/NPC2 results in
Purkinje cell depletion from the cerebellum (76)
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with a characteristic wrinkled tissue paper appearance due to the accumulation of glucocerebroside
in tubular, bilaminar membrane structures (71,
72). These macrophages develop an eccentric
nucleus as the accumulation of storage material in
endosomes and lysosomes begins to exclude the
cytoplasm. Histochemical analysis of Gaucher
spleens has shown that glucocerebroside laden
macrophages are characteristically surrounded by
activated macrophages (15). The influx of activated
macrophages to the liver and spleen of Gaucher
patients and the resulting inflammation presumably contribute to the hepatosplenomegaly. The
infiltration of macrophages into the bone marrow
is believed to displace hematopoietic stem cells,
leading to reduced numbers of red and white blood
cells in peripheral blood (pancytopenia).
There are links between the pathophysiology
in Gaucher disease and altered macrophage
function. Gaucher patients display impaired innate immunity, with attenuated antibacterial
function (80). There have been reports of chronic
low-grade inflammation in patients with Gaucher disease, consistent with increased levels of
pro-inflammatory and anti-inflammatory cytokines and chemokines (1, 14). In fact, Gaucher
macrophages remain metabolically active despite the accumulated glycolipid, resembling alternately activated macrophages (15). Cells
isolated from Gaucher patients have been reported to have an upregulation of major histocompatibility complex class II molecules, which
may result from increased endocytosis and recycling to the plasma membrane (5). In addition,
serum chitotriosidase (53), CCL18 (14), and soluble CD163 (87) are elevated in Gaucher disease,
which are indicators of alternately activated
macrophages and the inflammatory condition.
Macrophage-derived cells appear to also have an
important role in the pathophysiology of other
lysosomal storage disorders, including glial cells
in mucopolysaccharidosis type III (119).
The development of enzyme replacement therapy for Gaucher disease involved the identification
of the cell surface mannose receptor as a targeting
system in macrophages. The internalization of the
glucocerebrosidase enzyme by macrophage mannose receptors was distinct from the mannose-6phosphate targeting utilized for enzyme uptake
and treatment in other lysosomal storage disorders. Enzyme replacement therapy has proven to
be an enormous success for patients with type 1
Gaucher disease, reducing the storage load, decreasing the size of the liver and spleen, and restricting the progression of bone pathology.
Moreover, it has also been shown to restore the
bactericidal function of macrophages in Gaucher
patients (80). The success of enzyme replacement
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Fabry disease
Fabry disease was first described as a skin disorder
(angiokeratoma) before Anderson and Fabry recognized that it was a systemic disease. Further
investigation into angiokeratomas revealed the underlying accumulation of glycosphingolipids in endothelial cells within small capillaries of the skin
(56). The gastrointestinal (6), retinal (30), renal (3),
cardiac (112), and neuronal (88) complications in
Fabry disease (Table 1) can be partially linked to
the malfunction of endothelial cells in the vasculature of these organs. Kidney pathology also appears to be mediated by additional mechanisms,
including podoctyte and tubulointerstitial injury.
Fabry patients can present with cardiac complications, including hypertrophic cardiomyopathy, arrhythmias, and valve defects (112). Although the
vascular endothelial cells of the Fabry heart store
lipid, resulting in hypertrophy, this cannot alone
account for the grossly enlarged size of the heart. It
has been proposed that cardiomyopathy may be
caused by over-proliferation of vascular smooth
muscle cells induced by a yet-to-be-identified factor in circulation (7). The globotriaosylceramide
storage in Fabry patients also alters signaling responses, causing reactive oxygen species production, oxidative stress, persistent vasodilatation, and
inflammation (104), all of which contribute to the
pathogenesis.
GM2 gangliosidoses
Pathology in the GM2 gangliosidoses is primarily
restricted to the brain, but hepatosplenomegaly is
also observed in Sandhoff disease (Table 1) (79).
Ganglioside storage in the brain of Sandhoff/TaySachs patients can lead to meganeurite formation
(uncontrolled dendriteogenesis) and impact on
neuronal cell function (79). Neuronal pathology is
also believed to result from abnormal glial cell
expansion and neuronal apoptosis (58, 111). The
neuronal damage correlates with activation of
microglia (117) and can further potentiate apoptotic signaling (12). In addition, the impaired phospholipid synthesis can contribute to axonal growth
defects and abnormal neuronal signaling (20).This
may also be a factor in the neurodegeneration that
has been observed in other lysosomal storage
disorders.
I-Cell Disease
In 1967, Leroy and DeMars used the term “I-cell”
(FIGURE 2) to describe patient fibroblasts that contained characteristic inclusion bodies (73). I-cells
were shown to have reduced amounts of intracellular acid hydrolase activities but hyperactivity of
these hydrolases in the culture medium. I-cell patients also have high levels of circulating acid hydrolases in body fluids (123), suggesting excessive
secretion of lysosomal enzymes. Similar inclusion
bodies were observed in cells from patients with
another condition, Pseudo-Hurler polydystrophy.
These patients had later onset and slower disease
progression than the patients with I-cell disease
(Table 1). By 1975, there was strong appreciation
that I-cell disease (73), mucolipidosis type II (109),
and mucolipidosis III were all different forms of
the one disease (82).
The hyper-secretion of multiple lysosomal enzymes from I-cells suggested a common defect in
processing and targeting for these hydrolases
(116), which is now known to involve a deficiency
in the carbohydrate processing enzyme, N-acetylglucosamine-1-phosphotransferase (47). This cisGolgi localized enzyme is responsible for the
modification of N-linked high mannose oligosaccharides on newly synthesized lysosomal hydrolases. This processing event generates the key
mannose-6-phosphate targeting motifs that are involved in the intracellular delivery of certain soluble enzymes to lysosomes. Failure to generate this
targeting motif results in the constitutive secretion
of many soluble lysosomal hydrolases, reducing
the amount of intracellular hydrolase activity and
resulting in reduced substrate degradation.
The N-acetylglucosamine-1-phosphotransferase
is synthesized from two different gene products,
which give rise to an ␣2␤2␥2 multi-subunit enzyme. The attenuated form of I-cell disease (mucolipidosis III) has been attributed to molecular
lesions in the ␥-subunit, whereas classical I-cell
disease (mucolipidosis II) appears to be mainly
due to mutations affecting the ␣- and ␤-subunits.
From early studies, it was evident that N-acetylglucosamine-1-phosphotransferase was deficient in
all tissues, but the pattern of storage did not match
the pathogenesis (82, 83). It was recognized that
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and is likely to disrupt cellular signaling and trafficking events in other neurons.
Abnormal lipid distribution in Niemann-Pick
disease affects macrophage function, causing increased macrophage tissue infiltration and visceral
pathology. Pulmonary pathology has been related
to excessive macrophage recruitment and the overproduction of inflammatory chemo-attractants,
which in turn impact on lung surfactant regulation
(61). Macrophage infiltration has also been observed in the liver and spleen of Niemann-Pick
patients and, along with defective apoptotic signaling, is likely to contribute to the pathology in these
organs (108). The macrophage-related pathophysiology that is common between the lipidoses, may
be important in other lysosomal storage disorders,
particularly where phagocytosis is involved in
clearing damaged cells and undegraded substrate.
109
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Multiple Sulphatase Deficiency
The early history of multiple sulphatase deficiency
(FIGURE 2) is not clearly delineated, partly because
of its interrelationship with the metachromatic
110
PHYSIOLOGY • Volume 25 • April 2010 • www.physiologyonline.org
leukodystophy disorders, but also because it
represents a protein processing defect that was
difficult to discern biochemically. Multiple sulphatase deficiency patients display biochemical
and clinical symptoms (Table 1) that are consistent
with a combination of different individual sulphatase
deficiency disorders (89). The net result of the deficiency in a range of sulphatases is the storage
of glycosaminoglycans, sulphatides, and gangliosides. In 1979, it was postulated that a common
sulphatase posttranslational processing modification was the most likely explanation for the deficiency (9, 57). The identification of the conserved
active site cysteine residue in sulphatases was a key
step in unraveling the molecular basis of multiple
sulphatase deficiency. This crucial amino acid is
posttranslationally modified in sulphatases to generate unique C␣-formylglycine residues (105). The
sulphatase modifying factor gene (SUMF1) was
identified and characterized (28, 34, 70, 126), leading to an understanding of the molecular basis for
this disorder.
The finding that multiple sulphatase deficiency
patients express structurally stable but catalytically
inactive sulphatase enzymes guided subsequent
studies on sulphatase cell biology. Multiple sulphatase deficiency provided the pathophysiological evidence for one of the key aspects of
sulphatase biology, the posttranslational protein
processing of sulphatase active site residues in the
endoplasmic reticulum. This disorder also aided in
shaping the concept of the structural similarity
between sulphatases, which was further substantiated by the resolution of the crystal structure for
several of the sulphatases (13).
Hypomelanization/Albinism
Syndromes
Hereditary albinism syndromes were initially recognized due to a dysfunction in the lysosomerelated organelles (FIGURE 2), melanosomes. In
1943, Beguez Cesar recognized Chediak-Higashi
syndrome (10). Chédiak linked the albinism in
these patients with anomalies in leukocytes and
recurring infections (24), whereas Higashi made
the seminal observation of giant peroxidase-granules in patient blood cells (51). In 1959, Hermansky-Pudlak syndrome (49) was described, with
patients displaying symptoms similar to ChediakHigashi syndrome. Tissues from these albinism patients showed evidence of storage material in
endosomes and lysosomes, but unlike traditional
lysosomal storage diseases this defect was attributed to altered organelle biogenesis and traffic
rather than to the loss of a specific lysosomal hydrolase activity. Griscelli syndrome is also a member of this albinism group of disorders (59). Clinical
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mesenchymal cells exhibited extensive storage,
whereas the enzyme deficiency in non-mesenchymal cells did not exhibit storage. This gave rise to
theories that there may be other targeting mechanisms for lysosomal enzyme delivery (83).
Lysosomal enzyme and protein analysis in Icells have demonstrated 1) reduced amounts of
␣-mannosidase, ␤-hexosaminidase, 4-sulphatase,
iduronate-2-sulphatase, ␣-L-iduronidase, ␣-galactosidase, ␣-D-glucosidase, and ␣-fucosidase; 2) no
change in acid phosphatase; and 3) variable effects
on arylsulphatase A and ␤-galactosidase. These
variable effects on hydrolases indicated which enzymes are reliant on the mannose-6-phosphate
targeting system for traffic to the lysosome. In
addition, the increased amount of lysosomal membrane protein LAMP-1 in lysosomes and mannose6-phosphate receptors retained in the trans-Golgi
of I-cells demonstrated that there are changes to
lysosomal cell biology that ensue from the primary
defect.
The characteristic histological feature for I-cell
disease is the abundant membrane-bound vacuolar structures in mesenchymal cells, which have
either electron-lucent or fibrillogranular contents
(FIGURE 3). In older patients, lamellar lipid-like
material (FIGURE 3, B AND C) has been observed
within cytoplasmic inclusions. The vesicular structures in I-cell disease vary, with fibroblasts having
more pleomorphic and non-electron-lucent contents (82, 83) and endothelial cells having contents
with a concentric ring appearance (4, 75). This
combination of vesicular structures in fibroblasts
and endothelial cells appears to be unique to I-cell
disease and of diagnostic significance. The characteristic pattern of storage in I-cell neurons does not
correlate with the increased psychomotor retardation observed in classical, compared with attenuated, I-cell patients (83). Neurons of the cerebral
and cerebellar cortex from patients with classical
I-cell disease appear to exhibit only minimal storage, whereas anterior horn neurons (83) and spinal
ganglia neurons (90) exhibit numerous zebra body
inclusions (FIGURE 3C). This diversity in patterns
of substrate storage is presumed to reflect different
degrees of substrate turnover in different tissues,
together with the different biology of the substrates. In I-cell disease, the mistargeting of multiple lysosomal hydrolases results in a very rapid
onset disorder, with clinical symptoms that can be
evident in other lysosomal storage disorder patients (Table 1).
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symptoms in these disorders include hypopigmentation of the skin, eye, and hair (hyperpigmentation of melanocytes and hypopigmentation of
keratinocytes), prolonged bleeding (platelet dense
granule deficiency), neurodegenerative traits, immunodeficiency, and early death (Table 1) (59).
Hermansky-Pudlak syndrome
Chediak-Higashi syndrome
Chediak-Higashi syndrome can be characterized
by multiple defects in specialized endosomes
and lysosomes. A current model for the regulation of vesicular fusion favors a role for the
Chediak-Higashi/LYST protein in limiting either
the homotypic or heterotypic fusion of early
endosomes and lysosomes (69). In ChediakHigashi syndrome, uncontrolled fusion or fission
in affected cells results in giant malfunctional
secretory lysosomes and other organelles, which
in turn impair cargo delivery (59). For example,
peroxidase appears to accumulate in giant granules instead of being delivered to phagosomes
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Hermansky-Pudlak syndrome is classified as a disease involving miss-sorting of a large cohort of
cargo proteins, resulting from the abnormal processing of intracellular vesicles (32). This protein
miss-sorting typically results in protein and lipid
not reaching correct destinations and causes substrate storage in endosomal compartments. For
example, in the BLOC-1 and BLOC-2 protein complex deficiencies, the tyrosinase-related protein-1
and copper transporter either accumulate in early
endosomes or, if delivered to melanosomes, are
retained due to defective exocytosis (32, 107). Hermansky-Pudlak syndrome can also be caused by a
defect in the AP-3 adaptor protein, which also affects intracellular sorting of tyrosinase-related proteins to melanosomes (59). The pathognomonic
histological features of Hermansky-Pudlak syndrome include storage of ceroid-lipofuscin-like
pigment in lymphocytes, circulating blood monocytes, and bone marrow macrophages. Enlarged
lipid-containing vacuoles contain particulate debris resulting from incomplete digestion of erythrocytes, which are a major substrate for reticular
macrophages (59, 122). Lung lamellar bodies are
affected in Hermansky-Pudlak syndrome and contain increased amounts of surfactant phospholipid
and hydrophobic proteins due to defects in secretion (44). This results in lung inflammation and
reduced survival due to emphysema. In a mouse
model of Hermansky-Pudlak syndrome, the misssorting of proteins from early endosomes to melanosomes has been shown to increase the cell
surface presentation of some lysosome-related
proteins, presumably due to the default cell surface
trafficking pathway (33).
(102). In immune cells from Chediak-Higashi
syndrome patients, the impaired delivery of major histocompatibility complex class II molecules
to the plasma membrane leads to altered antigen
presentation (59). The disruption to vesicular
traffic in Chediak-Higashi cells impacts on both
innate and adaptive immunity, causing symptoms of immune-deficiency. T cells accumulate
the cytotoxic T-lymphocyte antigen 4 (CTLA4) in
enlarged cytoplasmic vesicles instead of at the
plasma membrane, preventing the inhibition of
T-cell activation (8). This leads to the uncontrolled infiltration of T-lymphocytes and macrophages into several organs (8). Secretion defects
are responsible for the accumulation of enlarged
glucuronidase-containing lysosomes in the kidney of Chediak-Higashi/Beige mouse mutants,
and this correlates with lower amounts of enzyme secretion into the urine (17).
Griscelli syndrome
Griscelli syndrome has been associated with altered vesicular trafficking due to its affect on the
assembly of actin-based vesicular machinery, involving the GTPase Rab27a, melanophilin, and
myosin Va (59). Loss of any component of this
complex leads to melanosome clustering in the
perinuclear region of affected cells, rather than
delivery to keratinocytes, resulting in coat color
mutants in mice and partial albinism in humans
(86). Despite being caused by a different mechanism, Griscelli syndrome shares some pathophysiological features with other hypopigmentation
syndromes. This includes altered plasma membrane delivery, impaired secretion, and immune
deficiency (86).
The common aetiology in the albinism group of
syndromes relates directly to similarities in their
impact on the biogenesis and traffic of endosome
and lysosome organelles. Disruptions to the integrity of the endosome-lysosome vesicular trafficking
network can be at different points in this system
(FIGURE 1) but still manifest with common functional outcomes. The altered vesicular traffic observed in albinism syndromes has some similarity
with other lysosomal storage disorders, but in the
latter this is caused by secondary effects on lysosomal biogenesis that ensue from the primary enzyme deficiency and substrate storage.
Conclusions
Pivotal studies in the early to mid-1900s established the existence of the lysosome and led to the
concept of lysosomal storage disorders (FIGURE 2)
(31, 50). The subsequent investigation of the genetic, biochemical, and physiological aspects of
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111
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112
PHYSIOLOGY • Volume 25 • April 2010 • www.physiologyonline.org
2) transport across the lysosomal membrane; or
3) endosome-lysosome trafficking. We are beginning to understand how substrate storage impacts
on cellular function to cause disease pathogenesis.
As suggested by Walkley and coworkers, lysosomal
diseases may be better viewed as conditions of
molecular deprivation that result in specific pathogenic cascades (118, 119).
Intracellular traffic between different organelle
compartments is mediated through the formation
and movement of vesicles and is controlled by
specific targeting signals and trafficking machinery. By determining the function of proteins in
lysosomal diseases such as the albinism disorders,
we should increase our understanding of the normal trafficking mechanisms in cells. To this end,
genetic studies including gene ablation of orthologs, in organisms such as Danio rerio, Drosophila melanogaster, and Caenorhabditis elegans
are likely to uncover new components of vesicular
machinery that are critical for normal cell physiology (41). Vesicular traffic is central to the function
of endosomes and lysosomes, and the impact of
undegraded substrates on this important function
is only just beginning to be appreciated.
The ability to gain a complete understanding of
the pathogenesis in lysosomal disease will, in effect, involve a dissection of the functionality and
interrelationship of the entire endosome-lysosome
system. This knowledge will be critical if we are to
recognize the underlying molecular basis of storage disorder pathogenesis and how to utilize this
information to develop novel therapeutic strategies for these devastating disorders. 䡲
The authors thank Dr Janna Morrison for appraisal of this
manuscript.
The Cell Biology of Diseases Research Group is funded
by the National Health and Medical Research Council
(NHMRC), the Australian Research Council (ARC), and the
University of South Australia. E. J. Parkinson-Lawrence is
an NHMRC Peter Doherty Research Fellow. R. Plew is an
ARC Industry Research Fellow. D. A. Brooks is an NHMRC
Senior Research Fellow.
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