Brain Pathology ISSN 1015-6305

MINI-SYMPOSIUM: Autophagy Dysregulation in Neuropathology

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Autophagy in Lysosomal Myopathies

May Christine V. Malicdan1,2; Ichizo Nishino1
1 2

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Keywords autophagy, Danon disease, LAMP-2, lysosome, myopathy, Pompe disease. Corresponding author: Ichizo Nishino, MD, PhD, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan (E-mail: nishino@ncnp.go.jp) Received 1 November 2011; accepted 1 November 2011. doi:10.1111/j.1750-3639.2011.00543.x

Abstract
Lysosomal myopathies are hereditary myopathies characterized morphologically by the presence of autophagic vacuoles. In mammals, autophagy plays an important role for the turnover of cellular components, particularly in response to starvation or glucagons. In normal muscle, autolysosomes or autophagosomes are typically inconspicuous. In distinct neuromuscular disorders, however, lysosomes become structurally abnormal and functionally impaired, leading to the accumulation of autophagic vacuoles in myobers. In some instances, the accumulation of autophagic vacuoles can be a prominent feature, implicating autophagy as a contributor to disease pathomechanism and/or progression. At present, there are two disorders in the muscle that are associated with a primary defect in lysosomal proteins, namely Pompe disease and Danon disease. This review will give a brief discussion on these disorders, highlighting the role of autophagy in disease progression.

INTRODUCTION
Macroautophagy is a highly regulated process in the lysosomal pathway for the degradation of long-lived proteins and damaged or unneeded organelles in the cytoplasm, including mitochondria and endoplasmic reticulum (48). Autophagy is, in general, a mechanism by which cells respond to starvation, either because of decreased extracellular nutrients or intracellular metabolites (52). Macroautophagy provides the cells with additional energy or ATP sources by catabolizing macromolecules and organelles to generate metabolic substrates, thereby allowing for adaptive protein synthesis. Macroautophagy also functions to maintain the overall quality of the cytoplasm by getting rid of damaged organelles and protein aggregates, and plays a central role in development, immune response and cell differentiation. Although it has been established that autophagy is induced by various factors, recent studies have demonstrated that autophagy could also occur spontaneously for renewal of the molecules and organelles (26). Dysfunctional autophagy occurs in many primary lysosomal disorders (3, 39), as well as in neurodegenerative diseases, cancer and inammatory diseases. As functional lysosomes are required to degrade cytoplasmic components, defects in lysosome function can lead to autophagic stress (5) characterized by accumulation of autophagic intermediates (23). On the other end of the spectrum, pathogenic induction of autophagy that leads initially to the maturation of autophagosomes, but eventually to dysfunction in maturation, can occur in myopathies (1, 24). Macroautophagy occurs both in physiologic conditions and in disease. In skeletal muscles and neuronal tissues, autophagy has been found to be physiologically enhanced (27). Disorders in which autophagic vacuoles are seen in the skeletal muscles are generally referred to as autophagic vacuolar myopathies (AVMs) (21, 24, 32,
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33, 42, 51), which include two known primary lysosomal disorders: Pompe disease and Danon disease (30). Despite the observation that the generation of autophagic vacuoles can be remarkable in skeletal and/or cardiac muscles, their precise relevance in each disorder and the mechanism by which they are formed remain to be claried. In this review, we will focus on primary lysosomal protein deciencies and related myopathies, highlighting the role of autophagy in the pathomechanism of the diseases.

POMPE DISEASE (ACID MALTASE DEFICIENCY)

Pompe disease, also known as glycogen storage disease type II, is the prototypic autosomal recessive lysosomal storage disorder (36, 43) caused by a primary deciency of acid alpha-1,4-glucosidase or acid maltase. This lysosomal hydrolase, acid a-glucosidase (GAA; EC 3.2.1.3), is an exo-1,4- and -1,6-a-glucosidase that specically hydrolyzes glycogen to glucose. Deciency of GAA leads to accumulation of lysosomal glycogen in virtually all cells of the body, but the pathological effects are most notable in cardiac and skeletal muscles. Abnormal lysosomal glycogen accumulates in the myocytes of skeletal, cardiac and smooth muscle, and has been detected in fetuses as early as 1618 weeks gestation. Recently the estimated prevalence is around 1 per 40 000 live births.

Clinical features of Pompe disease

Pompe disease encompasses a broad spectrum of clinical phenotypes, ranging from severe infantile-onset to a seemingly benign, less progressive late-onset form (8, 16). The late-onset form is further divided into childhood, juvenile and adult types. The variety

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Figure 1. Subtypes of Pompe diseases and ndings in pathology. Hematoxylin and eosin staining (A) shows vacuolar structures (arrows) in myobers pathognomonic for the disease especially in infantile onset form. In childhood onset form, several vacuoles are scattered all throughout the sections. The late-onset form is characterized by milder changes, namely scattered inclusion bodies that may appear like rimmed vacuoles. The vacuolar structures are highly stained by acid phosphatase. Electron microscopy (B) shows that the vacuoles (double arrows) occupy the whole diameter of the ber and disrupt myobrillar structure.

in clinical features is largely caused by the large variety of mutations in the GAA gene. More than 50 mutations have been reported in the gene encoding GAA, leading to a total or partial deciency of lysosomal GAA. The level of residual enzymatic activity has been correlated with the location of mutations, age of disease onset and severity of disease, although a denite genotype-phenotype correlation cannot be made. Importantly, among all enzymes responsible for glycogen storage disease, GAA is the only enzyme that is localized in the lysosomes, whereas all other enzymes are present in the cytosol. Naturally, lysosomal abnormalities are seen only in Pompe disease among the glycogen storage diseases. In the most severe, infantile form of Pompe, disease may be apparent in utero but usually presents in the neonatal period with macroglossia, cardiomyopathy, hypotonia and respiratory insufciency. In untreated infants, death occurs around the rst year of life because of cardiorespiratory failure. In the late-onset disease, skeletal muscle weakness predominates, mostly involving the proximal limb muscles and the diaphragm, but there is usually no cardiac involvement. These patients often show respiratory insufciency even when they are still ambulant. There are also adult patients that present with very mild symptoms, often misdiagnosed as limb-girdle muscular dystrophy. Overall, there is an inverse correlation between disease severity and the level of residual

enzyme activity, with the most severely affected infants having no detectable enzyme activity. Complete deciency (activity <1% of normal controls) is associated with classic infantile-onset Pompe disease. On the other hand, partial deciency (activity that is 2%40% of normal controls) is associated with the non-classic infantile-onset and the late-onset forms (18). In terms of pathology, intracytoplasmic vacuoles are prominent in the infantile form of acid maltase deciency more than in the adult form (Figure 1A, rst column). Characteristically, these vacuoles so extremely large that these can occupy most of the space in many muscle bers, resulting in a lace-like appearance (Figure 1A,B). This peculiar appearance is almost pathognomonic in terms of histological diagnosis. These vacuoles contain amorphous materials that are presumably glycogen because of the strong reactivity with periodic acid Schiff stain. Acid phosphatase staining also shows strong signals in these vacuoles, indicating high lysosomal content (Figure 1A). The ndings on late-onset forms may be more subtle, mostly consisting of a few acid-phosphatase inclusions (Figure 1A, last column).

Enzyme replacement therapy for Pompe

Enzyme replacement therapy (ERT), using recombinant human GAA, is now available (2) and has been demonstrated to be effec83

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tive in infantile cases, although some, studies showed that ERT can also benet some patients with the late-onset form to some extent. It is generally believed, however, that ERT would be more effective when it is given early in the course of symptom development and before irreversible muscular damage has occurred, where increased cytoplasmic glycogen released from lysosomes is probably inaccessible to the membrane receptor-dependent targeting mechanism (17). It is peculiar that the ERT clears lysosomal storage disorder in the heart but not efciently in skeletal muscles, in both humans and in the GAA-/- mice, where glycogen accumulation persists even when the enzyme activity reaches normal or near normal levels in muscle (22, 28, 35). This has been attributed to the autophagic build-up in muscle, evidenced by the large pools of autophagic debris in addition to the enlarged glycogen-lled lysosomes in therapy-resistant fast-twitch (type II) muscle bers (37, 15). In the GAA -/- mice, in addition, the lack of response is also complicated by the fact that a large portion of the therapeutic enzyme is diverted to the area of autophagic accumulation (13). Recent studies have claried why autophagic build-up is more remarkable in type II muscle bers (37). The cellular pathology in this disease affects the pathways involved in both endocytic and autophagic processes. Raben et al have reported the dramatic expansion of endocytic vesicles, decrease in mobility of late endocytic vesicles and increase in luminal pH in a subset of late endosomes/lysosomes in GAA knockout myoblasts. Using isolated single bers from these mice, they demonstrated that type 2 bers contain large regions of autophagic build-up spanning the entire length of the bers. In addition, they found out that type 2 bers were resistant to ERT, and this phenomenon is probably inuenced by the low amount of proteins involved in endocytosis and trafcking of lysosomal enzymes, combined with increased autophagy in these bers. Furthermore, it was evident on electron microscopy that type 1 bers contained only occasional double-membrane autophagosomes, whereas in type 2 bers the autophagic regions contained vesicles with morphological features representative of various stages of the autophagic process. In addition, the intracellular microtubule network is disorganized in the area of this autophagic build-up (15). The pathologic mechanism by which glycogen accumulation eventually causes muscle malfunction is not fully understood, but has been mainly considered secondary to the energy crisis in skeletal muscles because of failure in digesting lysosomal glycogen to glucose; as a result, muscle cells should be deprived of a necessary source of energy. But it is now becoming clear that in Pompe disease, failure of the lysosomal degradation of glycogen causes the extensive accumulation of various kinds of autophagic vacuoles leading to dysfunction of cellular trafcking, continuous autophagic build-up, and marked abnormality of cytoskeleton organization in muscle bers, which may enhance the autophagic process (14) and perturb muscle contractility. Upregulation or dowregulation of macroautophagy in an attempt to strike a balance between the need to maintain some level of autophagy and to inhibit it has been promising in some diseases like malignancy (4) and neurodegeneration. In Pompe disease, manipulation of macroautophagy has been shown to be effective in addressing the inefcacy of ERT in muscles (40). When Atg5, a key gene in the autophagic process, was selectively inactivated in the skeletal muscle of the murine Pompe model, autophagic build-up
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was indeed prevented but this exacerbated the clinical phenotype of the GAA-/- mice, despite a minimal decrease in muscle glycogen (38). In contrast, suppression of Atg7 specically in fast skeletal muscles led to the normalization of glycogen levels (39), indicating that suppression of autophagy alone can lead to a therapeutic benet in skeletal muscles. When combined with ERT, suppression of either Atg5 or Atg7 enhanced the correction on muscle glycogen storage, although there were biochemical and phenotypical differences observed between the two genetic manipulation strategies. It is, however, important to note that suppressing autophagy in the muscles can theoretically also have unwanted consequences, such as accumulation of dysfunctional mitochondria and oxidative stress (49), emphasizing the need to nd that balance when considering manipulating autophagy for treatment.

DANON DISEASE
Clinical features of Danon disease
Danon disease has been referred to as glycogen storage disease IIb (GSDIIb), but it is not actually a glycogen storage disease, as it is caused by the primary deciency of a lysosomal membrane protein, lysosome-associated membrane protein-2 (LAMP-2) (31). Danon disease is inherited as X-linked dominant; thus, males are more severely affected than females, although females develop symptoms at a later onset (29). Patients with Danon disease typically show a triad of ndings: hypertrophic cardiomyopathy; muscle weakness; and mental retardation (7). Muscle weakness and atrophy predominantly affect neck and shoulder-girdle muscles, but distal muscles can also be involved. Myopathy is usually mild and is evident in most male patients (90%), whereas it is seen only in only one third of female patients. All male patients have elevated serum creatine kinase (CK) levels, even those without apparent muscle symptoms. In contrast, serum CK is elevated in only 63% of female patients. Mental impairment is variable, but is usually mild in men whereas it is often not seen in women. Other organs like the liver (45, 47) and retina (34, 41) can also be involved. LAMP-2 is a single spanned membranous protein with molecular mass of 95120 kDa. The large luminal-ectodomain is highly glycosylated with some O-glycans and a large number of N-glycans, constituting about 60% of the total mass of these proteins and divided into two homologous domains by a hinge region (11). The transmembrane region is followed by a short C-terminal cytoplasmic tail. This cytoplasmic region has a well-conserved tyrosine residue, which is thought to provide a crucial signal for trafcking of LAMP-2 molecules to lysosomes. LAMP-2 has three isoforms, LAMP-2a, LAMP-2b and LAMP-2c. LAMP-2a functions as a receptor for chaperone mediated autophagy by selectively targeting substrates that contain a sequence motif related to the pentapeptide KFERQ for degradation in the lysosome (9, 25). LAMP-2b and LAMP-2c result from alternative splicing of exon 9. LAMP-2 is mainly localized in the limiting membranes of lysosomes and late endosomes and is also found in small amounts in early endosomal membranes and the plasma membrane. LAMP-2 is also spans the limiting membrane of late autophagic vacuoles. LAMP-2 is also detected in the lysosomal/endosomal lumen. It has been suggested that the luminal LAMP molecules are soluble, but

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it is also possible that these are associated with the internal membranes of lysosomes or endosomes (11). LAMP-2 is required for the maturation of early autophagic vacuoles by fusion with endosomes and lysosomes. Deciency of LAMP-2 leads to a failure in the normal progression of autophagic maturation, as the LAMP-2-decient hepatocytes exhibit accumulation of early autophagic vacuoles, intracellular mistargeting of lysosomal enzymes and LAMP-1, improper cathepsin D processing, abnormal retention of mannose-6-phosphate receptors in autophagic vacuoles, reduction of degradation of long-lived proteins, and resistance to induction of autophagic protein degradation after starvation (47). Although deciency in LAMP-2a-mediated chaperone mediated autophagy induces macroautophagy, the half life of autophagic vacuoles in complete LAMP-2-decient hepatocytes was prolonged, suggesting that retarded consumption was the cause of their accumulation (10). Skeletal muscles from the patients with Danon disease show scattered small basophilic granules in myobers, in addition to mild to moderate variation in ber size without necrotic or regenerative changes (46) (Figure 2A). Lysosomal acid phosphatase activity is enriched in these granules (Figure 2B), showing accumulation of lysosomal organelles in myobers. Autophagy-related proteins were also accumulated together with lysosomal proteins. Sarcolemmal proteins, like dystrophin and its associated proteins, extracellular matrix proteins and acetylcholine esterase, are recruited into large vacuolar structures surrounding those lysosomal granules. These structures are known as autophagic vacuoles with sarcolemmal features (AVSF) (Figure 3). On electron microscopy (Figure 2C), these larger AVSF vacuoles are lined with a layer of basal lamina and contain small autophagic vacuoles, multilamellar bodies, and electron-dense materials inside. Furthermore, vacuolar membranes with sarcolemmal features formed a closed space on serial sections (46). Therefore, the AVSF must be independent from the sarcolemma and the inner portion of AVSF should be topologically equivalent to the extracellular space. The mechanism by which this membrane is generated remains to be claried; sarcolemmal membrane indentation is unlikely, and de novo generation is most probable, especially in cases where mistransport of sarcolemmal proteins to intracellular vacuoles occurs. Another feature of this AVSF is an increase in its frequency with aging, and this is correlated with the progression of muscle weakness (46). Thus, AVSF may be a hallmark for progression of disease, at least in the skeletal muscle of Danon disease patients. A signicant number of patients with hypertrophic cardiomyopathy are associated with LAMP-2 mutation, emphasizing the importance of screening for mutations in this gene among patients with non-established etiology of cardiomyopathy (32). All Danon disease patients present with severe cardiac symptoms, which include cardiomyopathy with or without dysrhythmia, and sometimes patients succumb to cardiac failure. On histological observation, cardiomyocytes show severe vacuolation and degeneration, including myobrillar disruption and lipofuscin accumulation. The association of myopathy and LAMP-2 deciency has not been fully elucidated. The affectation of skeletal muscle is somehow deduced from ndings in the analysis of the heart in LAMP-2-decient mice (44), where cardiomyopathy was seen. In vitro force measurement of isolated cardiac trabeculae in LAMP2-decient mice showed signicantly lower twitch forces to half of those in wild type. Neuropathologic changes include variation

Figure 2. Pathology changes in Danon disease. Hematoxylin and eosin (A) staining shows moderate variation in ber size with small basophilic granules within the scattered myobers (arrows). These granules are highlighted with acid phosphatase (B). In electron microscopy, the autophagic vacuoles with sarcolemmal features (AVSF) appear to be lined with a layer of basal lamina (red arrows) and contain small autophagic vacuoles, multilamellar bodies and electron dense material (C).

in ber size and brosis, progressing as the mice age, in addition to the presence of increased lysosomal granules in most bers. Large clusters of small autophagic vacuoles are seen in the younger age, whereas large autophagic vacuoles are observed in older mice. Further attempts to analyze the whole function of LAMPs were done by using LAMP-1 and LAMP-2 double-decient cells from double gene knocked out embryos (12). The double-decient cells and, to a lesser extent, LAMP-2 single-decient cells, showed an
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Figure 3. Histochemistry and immunohistochemistry. Transverse sections of skeletal muscle biopsies from Danon disease patients. Several bers contain scattered tiny basophilic intracytoplasmic vacuoles (A): H&E. The vacuolar membrane has high nonspecic esterase (B) and acetylcholinesterase (C) activities. None of the vacuoles bind to a-bungarotoxin (D). Sections were stained with antibody against the C-terminus of dystrophin (E), the rod domain of dystrophin (F), the N-terminus of dystrophin (G), laminin a2 (H), a-sarcoglycan (I), b-sarcoglycan (J), g-sarcoglycan (K), d-sarcoglycan (L), dystrobrevin (M), a-dystroglycan (N), utrophin (O), dysferlin (P), b-dystroglycan (Q), perlecan (R), caveolin-E (S), collagen IV (T), bronectin (U), collagen VI (V), integrin b1 (W), and agrin (X). The vacuolar membranes were immuno-

positive with most of the primary antibodies, although reactivity of these proteins was variable. The results are summarized in Table 1. Transverse 5-mm serial sections (Y1Y5) and longitudinal section (Z) of muscle from Danon disease patient showing immunoreaction for dystrophin. Vacuolar membrane in muscle ber (*) is not connected to the sarcolemma but is closed. Longitudinal section shows that the vacuoles are spherical or oval. (DW, Y1Y5, Z): FIT C-labeled staining; (X): DAB staining, (CS, U, V, Y1Y5): serial sections. Scale bars: (AW, Y1Y5) = 20 mm; (Z) = 30 mm. Reproduced with permission from Kazuma S et al (2005) Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies. 64: 513522.

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accumulation of unesteried cholesterol in endo/lysosomal compartments as well as reduced amounts of lipid droplets. The cholesterol accumulation in LAMP-1 and LAMP-2 double-decient cells could be rescued by overexpression of murine LAMP-2a, but not by LAMP-1 (20), implying the role of chaperone-mediated autophagy. In LAMP-1 and LAMP-2 double-decient cells, the recruitment of RAB7 to phagosomes (19) is delayed, indicating that the progression of autophagic process does not occur smoothly. RAB7 has been localized to late endosomes and shown to be important in the late endocytic pathway. Considering all these results, the pathomechanism in Danon disease may not be entirely caused by the failure of lysosomal degradation systems. Rather, the structures created during the autophagic process or the autophagic vacuole formation may play a more active contribution to the cardiac dysfunction and muscle pathology. Similarly, macroautophagy induced in response to defects in chaperone mediated autophagy or mitochondrial toxicity appear to play detrimental roles in neurons (6, 50). This notion can be supported by the fact that there are more autophagic vacuoles in the cardiac muscles compared with skeletal myobers in the LAMP-2-decient mice, whose cardiac symptoms are more severe than the muscle weakness. Moreover, not only the numerous numbers of autophagic vacuoles but also the surrounding AVSF that occupy the center of myobers may disturb the function of muscles, and could lead to the ultimate destruction of myobrillar structures.

CONCLUSION
It is now becoming clear that neither the onset of symptoms nor the progression of disease in lysosomal autophagic myopathies result directly from the primary lysosomal enzymatic defect. Pompe disease can no longer be viewed simply as a glycogen storage disease. Increasing evidence now highlights that the functional pathology in Pompe disease is not entirely attributed to the accumulation of glycogen in lysosomes, but instead result from the massive accumulation of autophagic vacuoles, which has a profound effect on the myobrillar organization. These unwanted and undigested intracellular debris, as a downstream phenomenon to lysosomal dysfunction, can affect endocytic trafcking and prevent proper delivery of enzyme for therapy. In Danon disease, lysosomal dysfunction does not provide an adequate explanation for development of muscle weakness. Rather, the increase in autophagic vacuoles within the myobers disrupt myobrillar structures, ultimately leading to myober breakdown and loss of function.

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Brain Pathology 22 (2012) 8288 2011 The Authors; Brain Pathology 2011 International Society of Neuropathology