CHEMICAL BIOLOGY

Lysosomal Disorders

 

Doug A. Brooks, Molecular Medicine Sector, Sansom Institute, University of South Australia, Adelaide, Australia

Maria Fuller, Lysosomal Diseases Research Unit, Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, Australia

doi: 10.1002/9780470048672.wecb297

 

Lysosomal storage disorders are a group of over 50 different genetic diseases that result from lysosomal dysfunction. This disruption of lysosomal function can involve either a specific lysosomal hydrolase deficiency, a defect in lysosomal protein processing, or impaired lysosomal biogenesis. To appreciate the pathogenesis of lysosomal disorders fully, it is important to understand the dynamics of endosome-lysosome organelles, their capacity for the uptake and degradation of complex macromolecules, and how lysosomal biogenesis and hydrolysis are altered by substrate storage. The focus of this article will be on recognized lysosomal disorders and what is known about the composition and the function of endosome-lysosome organelles in these diseases. The lysosomal network will be discussed with a view to correlating the main site of endosome-lysosome degradation and the site of substrate accumulation in lysosomal disorders. A major unanswered question for lysosomal storage disorders is how an enzyme deficiency and the resulting storage of undegraded macromolecules impact on cells to cause organ dysfunction and disease.

 

A patient with possible Hurler syndrome was first described by Berkhan in 1907 (1), and it may be the first report of a lysosomal storage disorder. Nonetheless, the first detailed clinical description of a patient with a lysosomal storage disorder was by Charles Hunter, who described two brothers who are now recognized as having Hunter syndrome (2). Soon after this report, Meinhard von Pfaundler and Gertrud Hurler described Hurler-Pfaundler syndrome, which is now known as Hurler syndrome (3). A more detailed history of syndrome identification and the subsequent recognition of other lysosomal storage disorders have been documented by Whitley in 1993 (4).

In the 1960s, Hers and colleagues (5, 6) recognized that Pompe disease was caused by a deficiency of a-glucosidase and, using electron microscopy, evidence of storage vacuoles was reported. The identification of this enzyme deficiency, together with De Duve and colleagues’ description of lysosomes and their contents (7, 8), led to the concept of “lysosomal storage disorders.” This finding resulted in two seminal publications by Hers and Van Hoof that described “Lysosomes and Storage Diseases” (9, 10). It should be noted that much of the basic knowledge about the cell biology of lysosomes was contributed to strongly by these initial investigations on lysosomal storage disorders.

In 1999, Meikle and colleagues (11) reported the prevalence of lysosomal storage disorders as 1 in 7,700 live births for an Australian study that involved 27 different diseases. Since then, several new disorders have been recognized, and it is now accepted that, as a group, more than 50 different lysosomal storage disorders exist. Moreover, in some populations the prevalence of certain lysosomal storage disorders has been reported to be high, including 1 in 18,500 for aspartylglucosaminuria in the Finnish population (12) and 1 in 3,900 for Tay-Sachs in the Ashkenazi Jewish population (13). This finding led to past speculation that the combined incidence of lysosomal storage disorders may be as high as 1 in 1500 births (14), and more recent estimates suggest the prevalence is approximately 1 in 1000 births (http://www.science.org.au/sats2007/hopwood.htm). Lysosomal storage disorders are now recognized as a substantial group of genetic diseases that result in lysosomal dysfunction, leading to a failure to degrade specific substrates, which then accumulate in endosome-lysosome organelles.

 

Endosomes and Lysosomes

From early observations, De Duve defined lysosomes as cytoplasmic particles that were associated with a range of acid hydrolases (7). At the electron microscope level, membrane-bound vacuoles or compartments were recognized and shown to contain acid hydrolases that were detectable by cytochemical staining (15). The definitive description of a lysosome (16) includes a membrane-bound organelle compartment that is acidic and contains a range of mature acid hydrolases (e.g., proteases and glycosidases). This organelle represents the most distal compartment in the endocytic pathway (Fig. 1) and is distinct from the prelysosomal compartment and endosomal compartments based on the absence of mannose-6-phosphate receptors (the receptors that are responsible for the targeting and trafficking of soluble lysosomal enzymes; see below). Lysosomes are heterogeneous in size, shape, and composition, and they exhibit high density in organelle fractionation experiments. The lyso- some is the most distal compartment for lysosomal enzymes trafficking from the biosynthetic pathway. As defined by Storrie in 1988 (16), the lysosome must be the principal domicile of a “lysosomal protein,” but the presence alone of a lysosomal protein in an organelle structure does not necessarily establish that organelle as a lysosome (for example lysosomal proteins can also be detected in endosomes and phagosomes).

Lysosomes are now known to be essential organelles involved in the turnover and the reuse of cellular macromolecules such as proteins, lipids, glycoproteins, and glycosaminoglycans. Lysosomes have other diverse functional roles in immune function, pigmentation, signaling, cell adhesion/motility, and membrane repair, and essentially they are a dynamic interface with the extracellular environment. Numerous subcellular events are required for the synthesis and the delivery of functional degradative enzymes to lysosomes and for the assembly of functional lysosomal organelles (17). This process is referred to as lysosomal biogenesis, and the transport of newly synthesized lysosomal proteins proceeds through another set of organelle compartments called endosomes (Fig. 1).

Endosomes mediate the delivery of degradative enzymes from the biosynthetic compartments to both lysosomes and the extracellular milieu and function in the processing and transport of secretory products (Fig. 1). Endocytic organelles are also involved in the internalization and the delivery of material from the extracellular milieu and cell surface to compartments inside the cell (18, 19). These two main intracellular pathways from the biosynthetic compartment and cell surface are convergent (Fig. 1) (20). Other specialist compartments exist within the network of endocytic organelles, which include phagosomes that sequester cytoplasmic material, and organelles for turnover and recycling. This complexity of endosome and lysosome organelles necessitates strict control of targeting and trafficking events. Intracellular traffic between these compartments can occur through specific vesicle formation that involves budding and fusion of membrane to and from different organelles, but other types of transient interaction are possible (see below).

 

 

Figure 1. Intracellular organelles/compartments and some basic pathways of vesicular traffic involved in lysosomal biogenesis and function. Lysosomal enzymes are synthesised in the rough endoplasmic reticulum (RER) and then traffic via the endoplasmic reticulum intermediate compartment (ERIC, involved in the retrieval of processing proteins back to the RER), to the Golgi. After glycoprocessing in the Golgi, soluble lysosomal proteins may then either exit the cell by the default secretory pathway in secretory vesicles (SV) or be targeted from the trans-Golgi network (TGN) by a mannose-6-phosphate receptor system to endosome compartments (sorting endosome, SE; late endosome, LE) for delivery to lysosomes (L). Soluble lysosomal enzymes may also traffic from the cell surface to the lysosome via a sorting and late endosomal pathway. Lysosomal membrane proteins can traffic by both of the latter intracellular routes, from either the trans-Golgi or the cell-surface to lysosomes, but cytoplasmic-based, tail sequence-targeting mechanisms are used to control this traffic.

 

Components of Endosomes and Lysosomes

One crucial role of the membrane that encloses the endosomal and lysosomal compartments is the isolation of the potent acid hydrolases that are key constituents of these compartments (21). The limiting membrane of lysosomes has proteins involved in membrane structure, compartment acidification (ATPase), ion transport, and vesicular traffic. Approximately 20-30 major polypeptides of molecular mass 15-200 kDa exist in lysosomal extracts, and most of these are highly glycosylated (16, 22). Typically, the mannose-6-phosphate receptors that target luminal lysosomal proteins are absent from the end-stage lysosomal compartment but are present in endosomes. The lysosome is composed of at least 20 known membrane proteins and over 50 luminal lysosomal proteins (22). The 50 or more known lysosomal storage disorders mostly relate to a dysfunction of one or more of the soluble acid hydrolases that are normally involved in macromolecular break-down, which includes proteases, glycosidases, sulphatases, phosphatases, and lipases. However, several lysosomal storage disorders involving membrane proteins, transporters/channels, and altered vesicular trafficking machinery have been recognized (23).

The major lysosomal associated membrane proteins—LAMP-I and LAMP-II are type-1 integral membrane proteins; they have a single membrane-spanning sequence, a highly glycosylated luminal domain, and a short cytoplasmic tail sequence involved in targeting/trafficking (24). Two other major lysosomal integral membrane proteins—LIMP-I/CD63 and LIMP-II—are both type II integral membrane proteins, with four and two membrane-spanning domains, respectively. Newly synthesized LAMP and LIMP molecules traffic via the trans-Golgi network (from the biosynthetic compartment) to endosomal/lysosomal compartments based on either tyrosine (LAMP-I, LAMP-II, LIMP-I/CD63) or di-leucine (LIMP-II)- sorting signals in the cytoplasmic domains of these molecules (25, 26). At steady-state, most LAMP-I and LAMP-II molecules are localized to the limiting membrane of endosomes and lysosomes. However, LAMP-I and LAMP-II are also detected in autophagic vacuoles. A major proportion of LIMP-II molecules are localized to endosomes and seem to have a role in the biogenesis of these organelles (27). LIMP-I/CD63 is primarily localized to the internal membranes of endosomal vesicles of multivesicular bodies and, to a lesser extent, is found at the limiting endosome-lysosome membrane and cell surface. Functionally, LAMP-II has been shown to have an important role in autophagy and seems to have the capacity to compensate for a LAMP-I deficiency (28). The exact function(s) of LIMP-I/CD63 is unclear, but it seems to have a role in immune cell activation, where it is subsequently expressed at the cell surface. LIMP-I/CD63 is a member of the tetraspannin family of proteins (29), which have also been implicated in the control of membrane and cell volume, as well as cell adhesion, cell motility, and antigen presentation.

Specific membrane and membrane-associated proteins also control the organelle traffic and fusion events that are associated with the movement of proteins between different intracellular compartments. Membrane proteins of the secretory and endocytic pathways depend on sorting signals that reside in their cytoplasmic domains. Many proteins exhibit multiple signals that determine their passage along these diverse pathways. Therefore, the steady-state distribution of any given membrane protein is dictated by the specific combination of sorting signals in the protein and the interaction of these signals with specific recognition molecules (26). This intracellular network of organelles and vesicles (Fig. 1) is in constant and dynamic flux.

Glycerophospholipids, cholesterol, and sphingolipids are the essential building blocks for all eukaryotic cell membranes (30). The lysosomal membrane, like other eukaryotic membranes, is composed not only of highly glycosylated proteins but also is enriched in amphiphilic lipids (30, 31). The lipid and protein composition of the lysosomal membrane is believed to be very complex, and this complexity ensures selective degradation such that the lysosomal membranes remain intact. This finding has led to the assumption that at least two distinct pools of lipid exist in the lysosomal membrane (32). Glycosphingolipids are important components of lysosomal membranes, which are involved directly in lipid rafts, and these are involved in both membrane transport and signaling (31). The early studies on the glycosphingolipidoses (a subgroup of lysosomal storage disorders) suggested that aggregates of lipids accumulated as multivesicular storage bodies in lysosomal compartments (33, 34). Notably, cholesterol is normally enriched in the membranes of early endocytic organelles but not in lysosomes.

 

Targeting of Protein Constituents to Lysosomes

Most lysosomal proteins have either high mannose or complex oligosaccharide side chains that are attached to asparagine residues in the polypeptide at consensus (NXS, NXT sites: where N is asparagine, S is serine, T is tyrosine, and X is any amino acid) glycosylation sites (16, 35, 36). In the case of soluble lysosomal proteins, N-linked glycosylation is attached to the growing polypeptide chain in the endoplasmic reticulum, and this forms the basic structure that is modified to generate the mannose-6-phosphate targeting signals that are involved in targeting these proteins to the lysosome (37). This latter processing event occurs in the cis-Golgi apparatus and involves the enzyme N-acetylglucosamine-1-phosphotransferase, which adds an N-acetylglucosamine-1-phosphate to certain mannose oligosaccharides. The removal of the N-acetylglucosamine residue in the trans-Golgi exposes the mannose-6-phosphate targeting signal that then allows soluble lysosomal hydrolases to interact with mannose-6-phosphate receptors for trafficking to endosomes and delivery to lysosomes (reviewed in References 37-39).

Thus, within the lumen of organelle compartments, some integral membrane proteins act as cargo receptors that recruit soluble molecules for traffic within the network of organelles comprising the secretory, endocytic, and lysosomal pathways. For example, the cation-dependent mannose-6-phosphate receptor [CD-MPR; 46-kDa dimer, which requires calcium (40)] and cation-independent mannose-6-phosphate receptor [CI-MPR; 300-kDa, also called the IGF II receptor (38)] are involved in binding soluble lysosomal proteins in the trans-Golgi network for targeted delivery of these enzymes to the endosome-lysosome system. Mannose-6-phosphate receptors are type I glycoproteins (have a single transmembrane sequence) and recycle between the trans-Golgi network, endosomal compartments, and the cell surface. Surprisingly, this recycling process does not seem to depend on whether the receptor is loaded with ligand (41). Mannose-6-phosphate receptors normally release their lysosomal enzyme cargo molecules in the prelysosomal compartment as a result of the low pH environment (pH 5.0-6.0). The free mannose-6-phosphate receptor is then returned to the trans-Golgi for subsequent cargo delivery. Therefore, lysosomes are defined as acid hydrolase-rich organelles that lack both the CD-MPR and CI-MPR, which distinguishes them from endo- somes (42).

Sorting signals that are either tyrosine-based (NPXY, YXX: where N is asparagine, P is proline, and X is any amino acid) or leucine-based [(DE)XXXL(LI), DXXLL: (where D is aspartic acid, E is glutamic acid, L is leucine, I is isoleucine, and X is any amino acid] are found within the cytosolic domains of transmembrane proteins (26). Sorting occurs through coated areas of membranes comprised of proteins such as the adaptor protein (AP) complexes and Golgi gamma ear adaptin (GGA 1-3) proteins, which act to bind targeting motifs (26). The NPXY motif, which is found within a subset of type I membrane proteins, mediates internalization from the plasma membrane alone. The YXX motif is found in the CI-MPR and the CD-MPR, LAMP-1, LAMP-2, and CD63, and it is involved in a wide variety of sorting processes. Positioning of the motif relative to the membrane is also critically important for the recognition of these targeting signals. The YXX-AP-2 interaction is facilitated by a conformational change induced by phosphorylation, which is part of targeting regulation. The dileucine signal (DE)XXXL(LI) found in many type I, type II, and multispanning proteins also binds to AP complexes. The LL and LI motifs exhibit a distinct preference for the complexes that are critical for the fine specificity of targeting. The DXXLL motif is found within several transmembrane receptors, CI-MPRs and CD-MPRs, which cycle between the trans-Golgi network and the endosomes. Mannose-6-phosphate receptors bind the VHS domain of GGA proteins only via this signal, which is regulated by phosphorylation of serine residues. GGA1 and GGA3 also have the DXXLL motif within their hinge regions. Binding the hinge region with the VHS domain invokes an auto-inhibitory effect. Phosphorylation of the GGA serine results in auto-inhibition and transfer of the mannose-6-phosphate receptors from GGA1 to AP-1. Ubiquitin has been shown to be involved in sorting at the cell surface, endosomes, and trans-Golgi network. Endocytic proteins, which include epsin, Hrs, and STAM, have a ubiquitin-interacting motif that binds directly to ubiquitin, which suggests that they could act as adaptors for sorting ubiquitinated cargo at discrete intracellular sites (26).

 

Interaction of Endosomes and Lysosomes and the Site of Substrate Hydrolysis

Many ligands that enter the endocytic pathway via receptor interaction are either sorted for traffic along specific organelle pathways (Fig. 1) or transit to the late endosome where ligands are dissociated from the receptors by the acid pH environment. For lysosomal enzymes, this dissociation event from mannose-6-phosphate receptors allows additional traffic to the most distal element of the endocytic machinery, the lysosomal compartment. A constant flux of membrane proteins seems to occur between late endosomes and lysosomes (43). It has been postulated that lysosomes fuse with endosomes to form a transient compartment that seems to be the major organelle involved in macromolecule degradation [i.e., “the cell stomach” (44)]. This finding implies that lysosomes are effectively a reservoir for acid hydrolases that are then tapped when required, whereas the late endosome is the degradative compartment. Moreover, lysosomal constituents can be recovered from the prelysosomal compartment and reformed as a lysosomal organelle (43). This theory helps to explain the heterogeneity of endocytic organelles, but it is consistent with the initiation of proteol- ysis/hydrolysis of macromolecules in endosome and prelysosomal compartments. The molecular machinery that mediates these vesicular traffic, fusion, and budding processes is yet to be defined fully. However, studies on a FYVE finger protein localized to early endosomes called Hrs and the endosomal-sorting complex required for transport (ESCRT) have indicated that a group of proteins that recognize ubiquitin motifs are involved directly in endosomal sorting and recruitment of proteins into multivesicular endosomes (45-48).

The mechanism for the transfer of endocytosed material between endosomes and lysosomes has generated many theories, which include maturation of endosomes into lysosomes, vesicular transport between endosomal and lysosomal compartments, transient interaction via channel formation (“kiss and run”), and direct fusion (44). Depending on the cargo involved, all of these mechanisms seem to be used (perhaps in different degrees) to regulate the level of hydrolytic capacity in any given compartment. Thus, lysosomes can interact with not only endosomal compartments but also phagosomes, autophagosomes, and the plasma membrane to effect different functional roles. For a lysosomal storage disorder, this model of lysosomal function would predict that endocytic cargo, such as glycosaminoglycan that is destined for degradation after internalization from the cell surface, would be delivered to a late endosome for degradation. In an attempt to degrade the substrate, lysosomes would either infuse lysosomal hydrolases into the late endosome and/or fuse directly to the late endosome to generate a hybrid organelle. The latter would provide maximum delivery of hydrolases, and a mechanism by which the cell could try to compensate for the reduced catalytic capacity that develops from a hydrolase deficiency. However, a failure to degrade the substrate contents may result in the maintenance of these hybrid endosome-lysosome organelles.

Evidence that the latter model of endosome-lysosome fusion and lysosomal recovery is valid comes from the lysosomal storage disorder mucolipidosis type IV (MLIV), which involves a defect in a Ca++ channel that seems to prevent the retrieval of lysosomes from the hybrid organelle (49). Thus, intra-organelle Ca++ is presumed to be required for the condensation process that leads to lysosomal organelle reformation. The trafficking of the glycosphingolipid lactosylceramide is inhibited in MLIV and, in common with other lipids, it may then accumulate inappropriately because of this blockage. In other lysosomal storage disorders that involve a hydrolase(s) deficiency, the failure to degrade intraorganelle substrate(s) may signal an incomplete process of degradation and, in the same way, potentiate the hybrid organelle and lead to the same adverse effects on cell function. Similarly, a defect in the organelle trafficking machinery can also impact on endosome-lysosome degradation to generate similar compartments, which also then accumulate undegraded storage material. Thus, a recent report of a defect in the endosomal sorting complex required for transport (ESCRT-III) machinery (50) impacts directly on late endosomes (multivesicular bodies), which generates compartments with a morphology remarkably similar to that observed in other lysosomal storage disorders that are caused by hydrolase deficiencies (e.g., Sanfilippo syndrome). This finding raises questions about the similarity between the vesicular pathology in different lysosomal storage disorders and whether common points for pathogenesis lead to similar clinical outcome.

 

Commonalities for Lysosomal Storage Disorders in Terms of Clinical Phenotype and Vesicular Pathology

Most patients with lysosomal storage disorders are born with no clinically obvious signs of disease, but in the severe forms of the disease, onset and progression of symptoms is rapid. In most cases, the severe form of each disorder is devastating (see Table 1) (51, 52) and results in an early death. Lysosomal storage disorders have been classified based either on clinical presentation, substrates stored, or similarities in the defect (53). For the purposes of this discussion, we have grouped some representative examples of lysosomal storage disorders according to the type of defect: mucopolysaccharidosis (defects in glycosamino-glycan degradation), oligosaccharidoses (defects in glycoprotein and glycogen degradation), sphingolipidoses and lipidoses (defects in glycolipid degradation), and finally protein processing and transport defects (Table 1). Short stature, skeletal dysplasia, coarse facial features, joint problems, visceromegaly, cardiac disease, CNS (central nervous system) pathology, and early death are all common disease manifestations, but these features are not present in all disorders (Table 1). This finding implies that a common mechanism for pathology may occur in some disorders, but some unique features presumably relate to the type of substrate being stored and/or the relative organ distribution and turnover rate of the substrate.

Potentially compartment specific differences exist between each lysosomal storage disorder. For example, in Pompe disease, the storage of glycogen in endosome-lysosome organelles results from sequestration of cytoplasmic material and involves a phagasomal compartment. In contrast, other lysosomal storage disorders involve material that has undergone traffic from different endosome/phagosome compartments. Thus, compartment-specific storage effects may occur, although it may still result in a common molecular mechanism by impact at a certain point in the endosome-lysosome pathway. Some commonalities observed in lysosomal storage disorder pathology may result from substrate being turned over in similar organs. Thus, the rate of substrate turnover will impact directly on the level of storage and thus cell and organ dysfunction.

 

Table 1. A representative sample of 37 known (50 or more) lysosomal storage disorders and the common clinical symptoms observed in these patients at the severe end of the clinical spectrum (adapted from References 51 and 52)

 

Lysosomal Storage

Disorder

(Syndrome)

Enzyme dehciency

Substrate Stored

Clinical Symptoms (common in severe form)

 

Mucopolysaccaridoses: Defects in glycosaminoglycan degradation

Mucopolysaccharidosis I (Hurler, Hurler-Scheie and Scheie syndromes)

α-L-Iduronidase

HS, DS

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac disease, comeal clouding, CNS involvement

Mucopolysaccharidosis II (Hunter Syndrome)

Iduronate 2-sulphatase

HS, DS

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac disease, comeal clouding, CNS involvement

Mucopolysaccharidosis IIIA (Sanhlippo A syndrome)

Heparan N-sulphatase

HS

Coarse hair, CNS involvement, aggressive behaviour, dysmorphic features (+/—), skeletal dysplasia (+/—)

Mucopolysaccharidosis IIIB (Sanhlippo B syndrome)

α-N-Acetylglucosaminidase

HS

Coarse hair, CNS involvement, aggressive behaviour, dysmorphic features (+/—), skeletal dysplasia (+/—)

Mucopolysaccharidosis IIIC (Sanhlippo C syndrome)

Acetyl-CoA α-glucosamine N-acetyltransferase

HS

Coarse hair, CNS involvement, aggressive behaviour, dysmorphic features (+/—), skeletal dysplasia (+/—)

 

Mucopolysaccharidosis HID (Sanhlippo D syndrome)

N-Acetylglucosamine

6-sulphatase

HS

Coarse hair, CNS involvement, aggressive behaviour, dysmorphic features (+/—), skeletal dysplasia (+/—)

 

Mucopolysaccharidosis IVA (Morquio A syndrome)

N-Acetylgalactosamine

6-sulphatase

KS

Short stature, skeletal dysplasia, cardiac disease, comeal clouding

 

Mucopolysaccharidosis IVB (Morquio B syndrome)

β-Galactosidase

KS

Short stature, skeletal dysplasia, cardiac disease, comeal clouding

Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)

N-Acetylgalactosamine

4-sulphatase

DS, CS

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac disease, comeal clouding

 

Mucopolysaccharidosis VII (Sly syndrome)

β-D-Glucuronidase

HS, DS

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, CNS involvement, cardiac disease

Mucopolysaccharidosis IX

Hyaluronidase

HA

Short stature, joint stiffness

 

Oligosaccharidoses: Defects in glycoprotein and glycogen degradation

α-Mannosidosis

α-Mannosidase

α-Mannosides

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac disease, CNS involvement

β-Mannosidosis

β-Mannosidase

β-Mannosides

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac and renal disease, angiokeratoma, CNS involvement

α-Fucosidosis

α-Fucosidase

α-Fucosides Glycolipids

Skeletal dysplasia, joint stiffness, visceromegaly, cardiac disease, angiokeratoma, CNS involvement

Sialidosis

α-Sialidase (Neuraminidase)

Sialyloligosaccharides

Short stature, skeletal dysplasia, CNS involvement

Galactosialidosis

α-Sialidase, α-galactosidase, protective protein.

Oligosaccharides

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac and renal disease, CNS involvement

Aspartylglucosaminuria

Aspartylglucosaminidase

Aspartylglucosamine

Skeletal dysplasia, visceromegaly, CNS involvement

Schindler, Kanzaki

α-Galactosidase B

Galactosaminides Glycolipids

Cardiac and renal disease, angiokeratoma, CNS involvement

Pompe disease

α-D-Glucosidase

Glycogen

Muscle weakness, cardiac disease

 

Sphingolipidoses and lipidoses: Defects in glycolipid degradation

GM1 gangliosidosis

β-Galactosidase

GMl-gangliosides, oligosaccharides, KS, glycolipids

Cardiac disease, CNS involvement

GM2 gangliosidosis

(Sandhoff and Tay-Sachs)

Hexosaminidase A and B

GM2-gangliosides, oligosaccharides, glycolipids

CNS involvement, visual impairment

Gaucher

Glucocerebrosidase

Glucoceramide globoside

Bone disease, visceromegaly, CNS involvement (severe form)

Fabry

α-Galactosidase

α-Galactosyl sphingolipids, oligosaccharides

Heart and kidney disease, angiokeratoma, CNS involvement (recurrent stroke)

Wolman

Acid lipase

Cholesterol esters

Visceromegaly, CNS involvement

Nieman-Pick types A and B

Sphingomyelinase

Sphingomyelin

Visceromegaly, CNS involvement

Farber

Acid ceramidase

Ceramide

Nodular swelling around joints, hypotonia, visceromegaly, CNS involvement, angiokeratoma

Krabbe

Galactosylceramidase

Galactosylceramides

Spasticity, ataxia, weakness, hypotonia, CNS involvement

Metachromatic leukodystrophy

Arylsulphatase

Sulphatides

Weakness, hypotonia, psychoses, ataxia, CNS involvement, behaviour changes

Protein processing and transport defects

Multiple sulphatase deficiency

Endoplasmic reticulum sulphatase modifying factors → sulphatases

MPS, sulphatides, glycolipids

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, CNS involvement

Mucolipidosis II/III I-cell disease

Golgi

N-acetylagalactosamine

1-phosphtransferase → lysosomal hydrolases

Oligosaccharides and glycolipids

Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac disease, comeal clouding, CNS involvement

Mucolipidosis IV

Mucolipin 1, Ca++/cation ion channel

PC, PL, MPS, SL, gangliosides

Comeal clouding, CNS involvement

Sialic acid storage disorder

Salla disease

Sialic acid transporter

Sialic acid

Visceromegaly, renal disease, CNS involvement

Cystinosis

Cysteine transporter

Cysteine

Renal disease, CNS involvement

Cobalamine deficiency type F

Cobalamine transporter

Cobalamine

CNS involvement

Hermansky-Pudlak syndrome (disorders of lysosomal biogenesis)

 

AP3 adaptor protein, or BLOC-1-3 (biogenesis of lysosome-related organelle complex), or HOPS (homotypic vacuolar protein sorting or VPS class C complex).

 

Ceroid lipofuscin

Lung and kidney disease, oculocutaneous albinism, CNS involvement

 

Fronto-temporal dementia

Endosomal sorting complex required for transport (ESCRT) including CHMP2B

 

CNS involvement

HS, heparin sulphate; DS, dermatan sulphate; KS, keratan sulphate; HA, hyaluronic acid; PC, phosphatidylcholine; PL, phospholipid; SL, sphingolipid.

 

Primary and Secondary Storage Materials

Most known lysosomal storage disorders result from a single gene defect that results in the reduction of a single catabolic event, and hence the accumulation of a specific substrate. Although this concept is apparently simple, the reality is that the storage of a primary compound can result in a complex cascade of dysfunction (51). Glycosphingolipids such as the gangliosides GM2 and GM3, and unesterified cholesterol can, for example, accumulate after the deposition of undegraded glycosaminoglycans, and this accumulation is evident in the lysosomal storage disorders mucopolysaccharidosis types I, II, and III. Thus, progressive disease manifestations such as skeletal dysplasia, heart disease, and CNS dysfunction may be more the result of this secondary storage than from the primary storage material. In turn, these manifestations may reflect a general disruption to lysosomal dysfunction and account for some commonalities in clinical presentation for lysosomal storage disorders.

 

Impact of Storage on Vesicular Structure and Traffic

Secondary storage in response to a primary defect and its associated stored substrate suggests a common process of lysosomal dysfunction in some storage disorders. Thus, GM2 and GM3 gangliosides have been observed to not only accumulate in GM1 gangliosidosis, Tay Sachs, and Sandhoff patients, but also in a range of other storage disorders including mucopolysaccharidosis types I, II, and III, and Niemann-Pick type C (54). In these disorders, vesicular structures with characteristic multilamellar inclusions, membrane swirls, and internal vesicles have been observed, which resemble either autophagosome or multivesicular endosome structures (52). Moreover, in mucopolysaccharidosis type III, the storage compartments have been reported to contain different amounts of the primary storage material heparin sulphate, GM2, and GM3 gangliosides (54). In addition, spheroid structures that contain ubiquitin have been reported (54). Chloroquine toxicity also results in vesicular structures that have similar morphology, which include whorled inclusions of lipid, multivesicular endosome-like structures and zebra bodies. In turn, this toxicity has been reported to be almost identical to the vesicular pathology in Fabry disease (55). This commonality of vesicular structures and pathology could be explained by the general impact on lysosomal function created by the primary storage material. Although these examples involve an enzyme deficiency and could therefore tend to support this concept, other lysosomal storage disorders involve dysfunction in either membrane transporters or vesicular machinery, and they generate similar vesicular pathology. For example, a defect in the lysosomal transporter mucolipin-1 (the cation channel that is involved in calcium export and necessary for the recovery of lysosomes from late endosome-lysosome hybrid organelles) causes the storage of lipids and gangliosides in enlarged multiconcentric lamellar structures. Moreover, a dysfunction of the ESCRT-III vesicular machinery, which results in neuropathology, has also been reported to cause the formation of similar multivesicular structures in a mouse model and these vesicles are almost identical to that reported in a mouse model of mucopolysaccharidosis IIIA (56). Possible explanations for these commonalities in vesicular pathology might therefore include the impact of storage on a critical event in lysosomal function, such as vesicle formation/recovery or vesicular traffic.

 

Treatment Strategies and Ability to Correct Residual Pathology

Treatment strategies are available for lysosomal storage disorders and include hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, chemical chaperones, and gene therapy (recently reviewed in References (57-61)). In practice, however, the clinical spectrum observed in lysosomal storage disorders means that—at the present time—a single therapeutic strategy is unlikely to treat all sites of pathology effectively. Thus, hematopoietic stem cell marrow transplantation is used currently for many patients with neuropathology, but it is not optimal (not effective for some disorders) and has significant risks. Hematopoietic stem cell transplantation is currently recommended for patients at risk of cognitive impairment and has been evaluated in combination with enzyme replacement therapy (62). Enzyme replacement therapy by intravenous infusion is being used for patients at the attenuated end of the clinical spectrum, in some lysosomal disorders [e.g., MPS I (mucopolysaccharide) (58, 62)], but it is of limited use for the treatment of those disorders with neuropathology. Recently, small molecule therapeutic strategies have been employed as potentially alternative or adjunct treatment strategies (reviewed in Reference 61). For example, substrate deprivation therapy uses small molecule inhibitors to reduce substrate synthesis, whereas enzyme enhancement therapy has been investigated using chemical chaperones (63) to improve the folding of mutant protein and thus enhance the level of residual enzyme activity in patient cells. Both new therapeutic strategies have been investigated in Gaucher disease (64), and substrate reduction therapy is in clinical practice.

The complex pathology that can result from lysosomal storage makes it potentially difficult to treat all sites of pathology and particularly to clear residual pathology. Thus, in general, the earlier the treatment is implemented the more likely an effective therapeutic outcome will be achieved. The optimum treatment strategy to cure lysosomal storage disorders may be gene replacement therapy, but it is still in the developmental stages and will likely be a long way from widespread clinical practice. Nonetheless, therapeutic strategies that result in significant improvement in the quality of life for lysosomal storage disorder patients are in clinical practice.

 

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Further Reading

Fuller M, Meikle PJ, Hopwood JJ. Epidemiology of lysosomal storage diseases: an overview. In: Beck M, Mehta A, Sunder-Plassmann G, Widmer U, eds. 2006. Oxford PharmaGenesis Ltd. Oxford, UK.

Swiedler SJ, Beck M, Bajbouj M, Giugliani R, Schwartz I, Harmatz P, Wraith JE, Roberts J, Ketteridge D, Hopwood JJ, Guffon N, Sa Miranda MC, Teles EL, Berger KI, Piscia-Nichols C. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am. J. Med. Genet. 2005; 134:144-150.

Tollersrud OK, Berg T. Lysosomal storage disorders. In: Lysosomes. Saftig P, ed. 2005. Springer Science and Business Media, New York.

Wraith JE, Hopwood JJ, Fuller M, Meikle PJ, Brooks DA. Laronidase treatment of mucopolysaccharidosis I. BioDrugs 2005; 19:1-7.

Wraith JE. Lysosomal disorders. Semin. Neonatol. 2002; 7:75-83.

 

See Also

Glycosylation of Proteins in the Golgi Apparatus

Chaperones, Molecular and Chemical

Membrane Trafficking

Lysosomal Trafficking

Endocytosis, Receptor-mediated

Glycolipids, Synthesis of

Lysosome, Topics in Chemical Biology