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Biochemical Society Transactions (2010) Volume 38, part 6
Storage problems in lysosomal diseases
Jean Michel Heard1 , Julie Bruyère, Elise Roy, Stéphanie Bigou, Jérôme Ausseil and Sandrine Vitry
Retrovirus and Genetic Transfer Unit, Department of Neuroscience, Institut Pasteur, 28 rue du Dr Roux, 75015 Paris, France, and INSERM U622, Institut
Pasteur, Paris, France
Abstract
Biochemical disorders in lysosomal storage diseases consist of the interruption of metabolic pathways
involved in the recycling of the degradation products of one or several types of macromolecules. The
progressive accumulation of these primary storage products is the direct consequence of the genetic
defect and represents the initial pathogenic event. Downstream consequences for the affected cells include
the accumulation of secondary storage products and the formation of histological storage lesions, which
appear as intracellular vacuoles that represent the pathological hallmark of lysosomal storage diseases.
Relationships between storage products and storage lesions are not simple and are still largely not
understood. Primary storage products induce malfunction of the organelles where they accumulate, these
being primarily, but not only, lysosomes. Consequences for cell metabolism and intracellular trafficking
combine the effects of primary storage product toxicity and the compensatory mechanisms activated to
protect the cell. Induced disorders extend far beyond the primarily interrupted metabolic pathway.
Introduction
LSDs (lysosomal storage diseases) form a group of rare
inherited genetic defects of the metabolism, which is at the
same time well defined and extremely heterogeneous. More
than 50 disorders are recognized as LSDs. This number is
constantly increasing, and it is expected that more diseases, on
which knowledge is currently limited, will be considered to be
LSDs when better documented. Beyond genetic inheritance
and alteration of a metabolic pathway, criteria leading to the
identification of a disease as LSD rely on the combination of
defined biochemical and histological features.
Biochemical disorders in LSDs consist of the interruption
of metabolic pathways involved in the recycling of degradation products of one or several types of macromolecules.
As a consequence of inefficient recycling, imperfectly
degraded substances accumulate in cells with cascades of
deleterious repercussions. Substances accumulating as the
direct consequence of the genetic defect are the primary
storage products. They represent the initial pathogenic event,
which may result in both cell-autonomous defects and
environmental reactions, e.g. inflammation [1]. Downstream
consequences include the secondary accumulation of other
substances, the secondary storage products, which have
not always been molecularly identified. The histological
hallmark of LSDs is cell vacuolation (Figure 1A). With time,
cells in most severely affected tissues become progressively
clogged with cytoplasmic inclusions. Since inclusions contain
materials that cells are apparently unable to eliminate, and cell
Key words: autophagy, Golgi matrix protein 130 (GM130), lysosomal storage disease (LSD),
lysosome-associated membrane protein (LAMP), lysosome biogenesis, Rab GTPase.
Abbreviations used: GM130, Golgi matrix protein 130; LAMP1, lysosome-associated membrane
protein 1; LSD, lysosomal storage disease; MPS, mucopolysaccharidosis.
1
To whom correspondence should be addressed (email [email protected]).
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Authors Journal compilation vacuolation is clearly related to the storage process, inclusions
are often referred to as storage lesions.
Although storage products and storage lesions are the two
main characteristics of LSDs, the nature of their relationship
is not simple and is still largely not understood. In the present
review, we examine their complex links.
A problem of content
Almost every metabolic pathway aimed at recycling
substances produced by macromolecule degradation in
lysosomes has been involved in LSDs. Indeed, the most
convivial classification of LSDs relies on the nature of
affected macromolecules [2], and therefore, in most cases,
refers to specific storage products. These products may
be precisely identified, as, for example, in lipidoses or
MPSs (mucopolysaccharidoses), or poorly characterized, as
in neuronal ceroid lipofuscinoses.
Despite the fact that the metabolic defect concerns all
cells in the organism, depending on the affected pathway
and the specific metabolic activity of deficient cells, storage
products are preferentially generated in certain tissues, where
they predominantly accumulate and cause disorders. The
geographies of the accumulation of storage products and that
of the installation of storage lesions are largely superimposed.
Subsequently, the condition of the most affected organs
results in the clinical manifestations that specify the disease
type. For example, skeletal muscles are the most diseased
organs in Pompe disease, which affects glycogen degradation;
bone and joint development is impaired in MPS type VI
because of the interruption of dermatan sulfate catabolism;
and demyelination in metachromatic leukodystrophy is
associated with the accumulation of long-chain fatty acids
in the central nervous system.
Biochem. Soc. Trans. (2010) 38, 1442–1447; doi:10.1042/BST0381442
Lysosomes in Health and Disease
Figure 1 Storage lesions in the MPSIIIB mouse brain
Cortical fragments of a 9-month-old MPSIIIB mouse were processed for electron microscopy (A), immunofluorescence (B),
immunogold (C), Western blotting (D) or immunostaining (E). (A) Ultrastructural analysis show polymorphic distended
vesicles in neurons (two left-hand columns), microglial cells (third column) and astrocytes (right-hand column). Low (top
row) and high (bottom row) magnifications of the same fields are shown. Extreme left- and right-hand panels of the bottom
row show zebra bodies. Scale bars, 1 μm. (B) Parasagittal cortical sections immunolabelled for the lysosomal marker LAMP1
(in purple) and the neuronal marker NeuN (left, in green), the microglial marker CD11b (middle, in green) and the astrocyte
marker GFAP (glial fibrillary acidic protein) (right, in green) show comparable LAMP1 accumulation, notwithstanding marked
differences in the aspect of storage lesions in these three cell types. Images are confocal fluorescence micrographs. Scale
bars, 10 μm. (C) Ultrathin cryosection stained with anti-LAMP1 antibodies coupled to 10-nm-diameter gold particles reveal
LAMP1 in the limiting membranes of two storage lesions with different aspects (dark vesicle in the upper left corner and
clear vesicle in the middle). Scale bar, 0.5 μm. (D) Western blot analysis of brain protein extracts with anti-LAMP1 antibodies
show increased signal in the brain of MPSIIIB mice, as compared with wild-type mice. The LAMP1 signal was normalized
when the expression of the missing lysosomal enzyme α-N-acetylglucosaminidase was induced through adeno-associated
vector-mediated gene therapy directed to the brain (MPSIIIB+AAV-NaGlu). Molecular masses of LAMP1 signals are indicated
in kDa on the left. (E) LAMP1 overexpresion and correction after gene therapy were similarly observed after immunostaining
of MPSIIIB mouse cortical sections. Scale bars, 100 μm.
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Coincidence of storage products and storage lesions in
the same organs led to the notion that disease expression
results from cell disorders that are induced by cytoplasmic
inclusions, which are themselves caused by the accumulation
of storage products in the lysosomes, the organelles in
which these products are generated. This simple view
appears to be insufficient with regard to our current
knowledge of LSDs. Indeed, the accumulation of the
primary storage products is associated with more or
less severe malfunctioning of the organelles in which
they are produced and stored, inducing pathological
consequences beyond the primarily affected metabolic
pathway.
A problem of container
Examination of storage lesions by electron microscopy
confirmed the high heterogeneity of storage lesions, which
is already visible on standard pathology sections. Cell
inclusions are large structures with different types of content,
ranging from clear amorphous material, internal debris,
internal vesicles, membrane fragments, dense aggregates and
multilamellar structures occasionally forming zebra bodies
(Figure 1A). Ultrastructural studies not only showed that
storage lesions differed depending on the affected cell
type, but also provided evidence that multiple types of
inclusions coexisted in the same cell. Thus a given
type of primary storage product can be associated with
multiple types of storage lesions. Contrasting with their
polymorphism in individual disease, inclusions show similar
features in different LSDs. For example, zebra bodies were
observed in many LSDs. Thus different types of primary
storage products can be associated with similar storage
lesions.
The relationship between the primary storage products and
the storage lesions is therefore not a binary one. It involves
additional players, the secondary storage products. Assuming
that secondary storage products participate in storage lesions
accounts for the observation of different types of lesions
in different types of cell, since secondary storage products
probably differ depending on the cell type. On the other hand,
if cascades of events triggered in different diseases converge
to common biochemical alterations and to the accumulation
of common secondary storage products in different LSDs,
it is then understandable that similar lesions are observed
in different diseases. According to this view, storage is
not solely a problem of content, the accumulating primary
products, but also a problem of container, the organelles that
become unable to degrade and recycle certain substances as a
secondary consequence of primary storage. Malfunctioning
of the container leading to the secondary storage of a
variety of materials appears a common feature that specifies
LSDs.
The most likely problematic container is obviously the
lysosome. Consistently, lysosomal markers are associated
with storage lesions. Overexpression of the lysosomal
marker LAMP1 (lysosome-associated membrane protein
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Authors Journal compilation 1) is associated with many LSDs [3]. The association of
LAMP1 with intracellular inclusions was detected in various
cell types, notwithstanding the fact that these inclusions
showed very different aspects. For example, in the brain
of MPSIIIB mice, both inclusions in microglial cells, which
appear as clusters of rounded white drops, and inclusions
in neurons and astrocytes, which are frequently dark and
spread over the cell surface, were stained with anti-LAMP1
antibodies (Figure 1B). The ultrastructural detection of
LAMP1 immunoreactivity in the limiting membranes of
intracellular inclusions indicated that storage lesions are
related to lysosomes (Figure 1C).
Experimental evidence has actually been provided in
some LSDs that lysosomal functions were altered beyond
the metabolic pathway directly affected by the missing
protein. Early studies of MPSs documented the inhibition
of the catalytic activities of several lysosomal enzymes by
glycosaminoglycans, the primary storage products in these
diseases [4]. Cholesterol accumulation in Niemann–Pick
type C and other LSDs causes inhibition of lysosomal
sphingomyelinase [5] and lysosomal glucosylceramidase
[6]. In mucolipidosis IV, inhibition of the degradation
of lysosomal ABC (ATP-binding cassette) transporters
increases undegraded substrate overload [7]. Since the
fusion of lysosomes with late endosomes, phagosomes or
amphisomes is the terminal step of endocytosis, phagocytosis
and macro-autophagy respectively, a global deficiency of
lysosomal functions affects these pathways. Consistently,
alteration of fluid-phase endocytosis was reported in
Niemann–Pick type C disease [8], alteration of phagocytosis
in monocytes increases susceptibility to infection in patients
with Gaucher disease [9] or α-mannosidosis [10], alteration
of macro-autophagy was reported in several LSDs [11,12].
Depending on the disease, macro-autophagy appears to be
activated, as in Niemann–Pick C disease [13], neuronal ceroid
lipofuscinosis [14] or GM1 gangliosidosis [15], or deficient
as in mucolipidosis IV [16] or multiple sulfatase deficiency
[17]. In many cases, macro-autophagy is both activated and
deficient, as shown in the skeletal and cardiac muscles of mice
and patients with Pompe disease [18], and to a lesser extent as
a consequence of relative starvation in the liver of the mouse
models of MPSI and MPSVII [19]. In contrast, our studies
of brain tissues in the mouse models of MPSI, MPSIIIA and
MPSIIIB did not find any evidence of increased formation or
accumulation of autophagolysosomes, and dynamic studies
of macro-autophagy in MPSIIIB cultured neurons indicated
that this pathway was normally efficient.
According to the hypothesis of global lysosome malfunctioning, storage lesions in LSDs consist in deficient hybrid
vesicles, as documented in the Caenorhabditis elegans model
of mucolipidosis IV [20]. Hybrid vesicles result from the
fusion of lysosomes with late endosome, amphisomes or
autophagosomes that are loaded with materials meant for
degradation [21]. In LSDs, these vesicles swell, accumulate
and proliferate because they are unable to recycle materials
contained in their lumen. Lysosome biogenesis is regulated
through a gene network controlled by TFEB (transcription
Lysosomes in Health and Disease
Figure 2 Altered expression of GM130 and disorganization of the Golgi architecture in MSPIIIB mouse neurons
(A) Cortical fragments from a wild-type mouse (left-hand panel), or a 9-month-old MPSIIIB mouse (right-hand panel)
were processed for immunofluorescence to simultaneously reveal the neuronal marker Map2 (in purple) and the cis-Golgi
protein GM130 (in green). Increased and more tubular GM130 signals are visible in MPSIIIB mouse neurons. Images are
confocal fluorescence micrographs. Scale bars, 10 μm. (B) MPSIIIB cortical neuron cultures (day 10) were stained for
LAMP1 (in purple) and GM130 (in green). Storage vesicles located in neurites appear doubly positive. Images are confocal
fluorescence micrographs. Scale bars, 10 μm. (C) Ultrathin cryosections from 9-month-old MPSIIIB mouse cortex were
co-stained with gold-coupled anti-GM130 (10-nm-diameter particles arrows) and anti-LAMP1 (15-nm-diameter particles,
arrowheads) antibodies. GM130 antibodies stained Golgi stacks (G) and a LAMP1-positive storage vesicle (StV). Scale bar,
0.2 μm. (D) Ultrathin sections of cortical fragments from a 9-month-old MPSIIIB mouse show disorganized Golgi (G) adjacent
to storage vesicles (StV) in a neuron (left-hand panel) and an astrocyte (right-hand panel). Continuity between altered Golgi
saccules and storage vesicles is visible. ER, endoplasmic reticulum; m, mitochondrion. Scale bars, 0.5 μm.
factor EB). In response to storage, this factor co-ordinates the
transcriptional activation of lysosomal genes, leading to the
multiplication of engorged lysosomes and/or hybrid vesicles
[22].
A problem of delivery
Alteration of macro-autophagy was particularly well documented in Niemann–Pick type C disease, showing overexpression of beclin1, an early inducer of macro-autophagy
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[13]. Interestingly, studies of Niemann–Pick type C disease
also emphasized the possible role of membrane trafficking
defects in LSDs [23]. In Niemann–Pick type C cells, as well
as in glycosphingolipid disorders, the transport of cholesterol
and glycosphingolipids from the late endosomes to various
destinations, including the plasma membrane, is defective
[24]. Endocytic vesicles are immobile due to increased
amounts of the small GTPase Rab7 bound to membranes
[25,26] and to the inhibition of Rab4 [27]. Impaired cholesterol delivery is reversed by overexpressing various small
GTPases of the Rab family [28] or the ADP-ribosylation
factor Arf6 [29]. Cholesterol efflux out of the endosomal
recycling compartment is accompanied with Golgi retargeting of glycosphinglolipids. Defects in membrane traffic
and lipid metabolism are also associated with mucolipidosis
type IV, in which mucolipin-1, a lysosomal non-specific
cation channel, is deficient [30]. In MPSs, cholesterol
and glycosphingolipids accumulate in structures that are
distinct from glycosaminoglycan storage sites, suggesting
intracellular trafficking defects in addition to lysosome
disability [31]. These observations support the notion that
a number of LSDs are related to defects that have an impact
on lysosome biogenesis in addition to lysosome functioning.
Our recent findings in the cortical neurons of the MPSIIIB
mouse model suggest trafficking defects at a pre-Golgi, or cisGolgi, step of lysosome biogenesis. GM130 (Golgi matrix
protein 130) is a tethering protein which controls vesicle
trafficking in pre- and cis-Golgi compartments. It is also a
Golgi matrix component that forms molecular complexes
with vesicle coat proteins and cargo transporters, and which
plays essential roles in Golgi morphogenesis and nucleation
of microtubules at the Golgi surface [32–34]. We detected
GM130 in storage lesion membranes, which were also stained
for LAMP1 (Figures 2A–2C). These vesicles were immobile,
abundant in proximal and distal neurites, and resistant to
brefeldin A, a drug that induces Golgi collapse into the
endoplasmic reticulum. They were frequently associated
with disorganized Golgi ribbon structures (Figure 2D). Our
results suggest that storage lesions in MPSIIIB neurons
are related to aberrant Golgi saccules, which appear to be
unable to interact with adjacent intra-Golgi, downstream or
upstream compartments, and form a dead-end pathway that
gives rise to accumulating storage vesicles [35].
According to the trafficking defect models, it is not so
much the amounts of undigested products to be stored that
raise a problem, but rather the toxicity of these products
for basic cell biological functions, which results in aberrant delivery systems. Permanent residues left inside
inappropriate delivery containers progressively increase the
amounts of stored material and form storage lesions.
Perspectives
LSDs are progressive diseases in which the inefficient
recycling of macromolecules degradation products in
lysosomes is tolerated for long periods of time before
disorders compromise cell functions and survival. Tolerance
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Authors Journal compilation to cell disorders is presumably made possible through
the activation of compensatory mechanisms. Acute models
of LSDs, in which distinction can be made between the
consequences of primary storage product toxicity and
compensatory mechanisms, will presumably shed new light
on the relationship of storage products with storage lesions.
Acute models of Niemann–Pick type C [29] or mucolipidosis
IV [36 ] have recently been produced for this purpose in HeLa
cells. Observations performed shortly after the induction
of lysosomal disorders will probably help to decipher the
complexity of the intricate cascades of pathogenic events that
characterize LSDs.
Funding
This work was supported by the Agence National de la Recherche
[grant number ANR-08-MNP-023].
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Received 26 April 2010
doi:10.1042/BST0381442
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