Neurovisceral and Skeletal G
            <sub>M1</sub>
            -Gangliosidosis in Dogs with β-Galactosidase Deficiency

Alroy, Joseph; Orgad, U.; Ucci, Angelo A.; Schelling, Scott H.; Schunk, Kenneth L.; Warren, Christopher D.; Raghavan, Subharekha; Kolodny, Edwin H.

doi:10.1126/science.3925555

Cited by 51 publications

(28 citation statements)

References 15 publications

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“…The fact that no other structure comparable in size with the MLBs is present in the transfected cells identifies the large fluorescently labeled LAMP-2-and L-PHA-positive vacuoles as MLBs. Deficiency in lysosomal galactosidases and sialidases is associated with the accumulation of lamellar bodies, demonstrating that impaired lysosomal degradation of glycoproteins or glycolipids can be associated with the formation of lamellar bodies (Amano et al, 1983;Alroy et al, 1985;Allegranza et al, 1989;Ohshima et al, 1997).…”

Section: Role Of Lysosomal Degradation In Mlb Biogenesismentioning

confidence: 99%

Biogenesis of Multilamellar Bodies via Autophagy

Hariri

Millane

Guimond

et al. 2000

MBoC

161

142

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Transfection of Mv1Lu mink lung type II alveolar cells with ␤1-6-N-acetylglucosaminyl transferase V is associated with the expression of large lysosomal vacuoles, which are immunofluorescently labeled for the lysosomal glycoprotein lysosomal-associated membrane protein-2 and the ␤1-6-branched N-glycan-specific lectin phaseolis vulgaris leucoagglutinin. By electron microscopy, the vacuoles present the morphology of multilamellar bodies (MLBs). Treatment of the cells with the lysosomal protease inhibitor leupeptin results in the progressive transformation of the MLBs into electron-dense autophagic vacuoles and eventual disappearance of MLBs after 4 d of treatment. Heterologous structures containing both membrane lamellae and peripheral electron-dense regions appear 15 h after leupeptin addition and are indicative of ongoing lysosome-MLB fusion. Leupeptin washout is associated with the formation after 24 and 48 h of single or multiple foci of lamellae within the autophagic vacuoles, which give rise to MLBs after 72 h. Treatment with 3-methyladenine, an inhibitor of autophagic sequestration, results in the significantly reduced expression of multilamellar bodies and the accumulation of inclusion bodies resembling nascent or immature autophagic vacuoles. Scrape-loaded cytoplasmic FITC-dextran is incorporated into lysosomal-associated membrane protein-2-positive MLBs, and this process is inhibited by 3-methyladenine, demonstrating that active autophagy is involved in MLB formation. Our results indicate that selective resistance to lysosomal degradation within the autophagic vacuole results in the formation of a microenvironment propicious for the formation of membrane lamella. INTRODUCTIONMultilamellar bodies (MLBs) are membrane-bound cellular organelles, which vary in size from 100-2400 nm, are composed of concentric membrane layers, and frequently exhibit an electron-dense core. MLBs are found in numerous cell types where they function in lipid storage and secretion (Schmitz and Mü ller, 1991). In lung type II alveolar cells, MLBs function as secretory granules whose exocytosis results in the deposition of the tubular myelin forms of surfactant on the surface of the alveolae (Hatasa and Nakamura, 1965;Ryan et al., 1975;Williams, 1977). The surfactant film over the alveolar epithelium regulates the surface tension at the air-cell interface and protects the alveola from collapse during respiration (Haagman and van Golde, 1991).Although the secretory function of MLBs in type II alveolar cells is well established, the precise mechanism of MLB biogenesis remains unclear. Autoradiographic studies of murine type II alveolar cells of mouse lungs showed that although phospholipids labeled with [ 3 H]choline are delivered directly from the Golgi to the MLB, proteins metabolically labeled with [ 3 H]leucine are visualized within multivesicular bodies before delivery to MLBs (Chevalier and Collet, 1972). Surfactant proteins A, B, and C are delivered via multivesicular bodies to MLBs, and multivesicular bodies are proposed as th...

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Section: Role Of Lysosomal Degradation In Mlb Biogenesismentioning

confidence: 99%

Biogenesis of Multilamellar Bodies via Autophagy

Hariri

Millane

Guimond

et al. 2000

MBoC

161

142

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“…3. 28 [4][5][6][7][8][9] was counted using air-dried blood smears stained with May-Grünwald-Giemsa. Ophthalmologic examination and cerebrospinal fluid (CSF) analysis were performed and skeletal radiographs were obtained for dog Nos.…”

Section: Case Historiesmentioning

confidence: 99%

“…38 The disease has been described in a variety of species, including cats, cattle, sheep, mice, and humans. [1][2][3][4][5][6][7][8][9]12,14,16,17,[27][28][29]31,[33][34][35][36][37][38] Until now, the canine form has been found in English Springer Spaniels (ESS), 3,33 Portuguese Water Dogs (PWD), 3,35,36 mixed-breed Beagles, 34 and Alaskan Huskies. 28 In humans, the disorder is classified as infantile (type 1), juvenile (type 2), and adult (type 3) forms.…”

mentioning

confidence: 99%

GM₁-gangliosidosis in Alaskan Huskies: Clinical and Pathologic Findings

et al. 2001

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Abstract. Three Alaskan Huskies, two females and one male, were diagnosed with GM 1 -gangliosidosis. Clinically, diseased animals exhibited proportional dwarfism and developed progressive neurologic impairment with signs of cerebellar dysfunction at the age of 5-7 months. Skeletal lesions characterized by retarded enchondral ossification of vertebral epiphyses were revealed by radiographs of the male dog at 5.5 months of age. Histologic examination of the central nervous system (CNS) revealed that most neurons were enlarged with a foamy to granular cytoplasm due to tightly packed vacuoles that displaced the Nissl substance. Vacuoles in paraffin-embedded sections stained positively with Luxol fast blue and Grocott's method, and in frozen sections vacuoles were periodic acid-Schiff positive. Foamy vacuolation also occurred within neurons of the autonomic ganglia. Extracerebral cells such as macrophages and peripheral lymphocytes also displayed foamy cytoplasm and vacuolation. In the CNS of diseased animals, a mild demyelination and axonal degeneration was accompanied by a significant astrogliosis (P Ͻ 0.05) in the gray matter as compared with age-and sex-matched control dogs. There was also a significant loss (P Ͻ 0.05) of oligodendrocytes in the gray and white matter of affected animals as compared with controls. Ultrastructurally, the neuronal storage material consisted of numerous circular to concentric whorls of lamellated membranes or stacks of membranes in parallel arrays. GM 1 -gangliosidosis in Alaskan Huskies resembles ␤-galactosidase deficiency in other canine breeds, and these CNS disorders may be a consequence of neuronal storage and disturbed myelin processing.

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“…Similarly, neural stem cells isolated from adult human olfactory bulb biopsies contained self-renewing, multipotential neural stem cells as evidenced by clonal analysis (Pagano et al, 2000). Many neurologic diseases that may potentially benefit from NPC transplantation occur in the dog (Griffiths et al, 1981;Haskins et al, 1984;Alroy et al, 1985;Koppang, 1988;Fischer et al, 1998;Wenger et al, 1999). We recently found that defects in canine NPCs occur in a model of a lysosomal storage disease (Walton and Wolfe, 2007).…”

Section: Introductionmentioning

confidence: 99%

In vitro growth and differentiation of canine olfactory bulb-derived neural progenitor cells under variable culture conditions

Walton

Wolfe

2008

Journal of Neuroscience Methods

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The dog serves as a large animal model for multiple neurologic diseases that may potentially benefit from neural progenitor cell (NPC) transplantation. In the adult brain, multipotent NPCs reside in the subventricular zone and its rostral and caudal extensions into the olfactory bulb and hippocampus. The olfactory bulb represents a surgically accessible site for obtaining cells for autologous NPC transplantation. To model conditions that would occur for ex vivo gene therapy in the postnatal brain, NPCs were isolated from the canine olfactory bulb, expanded ex vivo under different culture conditions, and compared quantitatively for growth and immunophenotype. Under standard growth conditions, canine olfactory bulb-derived NPCs (OB-cNPCs) could be expanded nearly 500-fold in the time evaluated. Canine OB-cNPCs grown on poly-D-lysine (PDL) or on PDL-fibronectin had similar growth rates, whereas supplementation with leukemia inhibitory factor (LIF) resulted in significantly slower growth. However, when OB-cNPC cultures were grown on PDL-fibronectin or PDL supplemented with LIF, a greater proportion of cells with neuronal markers were generated upon differentiation.

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Neurovisceral and Skeletal G _M1 -Gangliosidosis in Dogs with β-Galactosidase Deficiency

Cited by 51 publications

References 15 publications

Biogenesis of Multilamellar Bodies via Autophagy

Biogenesis of Multilamellar Bodies via Autophagy

GM₁-gangliosidosis in Alaskan Huskies: Clinical and Pathologic Findings

In vitro growth and differentiation of canine olfactory bulb-derived neural progenitor cells under variable culture conditions

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Neurovisceral and Skeletal G M1 -Gangliosidosis in Dogs with β-Galactosidase Deficiency

Cited by 51 publications

References 15 publications

Biogenesis of Multilamellar Bodies via Autophagy

Biogenesis of Multilamellar Bodies via Autophagy

GM1-gangliosidosis in Alaskan Huskies: Clinical and Pathologic Findings

In vitro growth and differentiation of canine olfactory bulb-derived neural progenitor cells under variable culture conditions

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Product

Resources

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Neurovisceral and Skeletal G _M1 -Gangliosidosis in Dogs with β-Galactosidase Deficiency

GM₁-gangliosidosis in Alaskan Huskies: Clinical and Pathologic Findings