Comparative Pathology of Murine Mucolipidosis Types II and IIIC

Vogel, Peter; Payne, B. J.; Read, Robert W.; Lee, W.-S; Gelfman, Claire M.; Kornfeld, Stuart

doi:10.1354/vp.08-vp-0189-v-am

Cited by 5 publications

(6 citation statements)

References 13 publications

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“…In addition, osteoclasts contain a second type of lysosome enriched in the ubiquitously expressed lysosomal hydrolase cathepsin D. Disruption of the Man‐6‐P targeting pathway in Gnptab −/− osteoclasts leads to unregulated secretion of bone‐resorbing hydrolases, whereas cathepsin D continues to reach lysosomes in a Man‐6‐P‐independent manner. It will be interesting to investigate in future studies whether the osteoporosis phenotype in Gnptab −/− mice (44), as well as in patients with mucolipidosis II (i.e. with mutations in Gnptab ) (45–48), is the result, at least partially, of this abnormal secretion of acid hydrolases by osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Disruption of the Man‐6‐P Targeting Pathway in Mice Impairs Osteoclast Secretory Lysosome Biogenesis

Meel¹,

Boonen²,

Zhao³

et al. 2011

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Osteoclasts are specialized cells that secrete lysosomal acid hydrolases at the site of bone resorption, a process critical for skeletal formation and remodeling. However, the cellular mechanism underlying this secretion and the organization of the endo-lysosomal system of osteoclasts have remained unclear. We report that osteoclasts differentiated in vitro from murine bone-marrow macrophages contain two types of lysosomes. The major species is a secretory lysosome containing cathepsin K and tartrate-resistant acid phosphatase (TRAP), two hydrolases critical for bone resorption. These secretory lysosomes are shown to fuse with the plasma membrane, allowing the regulated release of acid hydrolases at the site of bone resorption. The other type of lysosome contains cathepsin D, but little cathepsin K or TRAP. Osteoclasts from Gnptab−/− mice, which lack a functional mannose 6-phosphate targeting pathway, show increased secretion of cathepsin K and TRAP and impaired secretory lysosome formation. However, cathepsin D targeting was intact, showing that osteoclasts have a mannose 6-phosphate-independent pathway for selected acid hydrolases.

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Section: Discussionmentioning

confidence: 99%

Disruption of the Man‐6‐P Targeting Pathway in Mice Impairs Osteoclast Secretory Lysosome Biogenesis

Meel¹,

Boonen²,

Zhao³

et al. 2011

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“…43 Feline ML II is spontaneously occurring, displays inclusion bodies in cultured fibroblasts, and shows skeletal and joint abnormalities, making the feline a better but still not ideal model that needs further study. 44 Studies of animal models of mucopolysaccharidosis VI suggest that proinflammatory cytokines alter expression of several matrix metalloproteinases, enzymes involved in ECM degradation.…”

Section: Phenotypeegenotype Correlationsmentioning

confidence: 99%

Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands

Cathey

Leroy

Wood

et al. 2009

Journal of Medical Genetics

137

163

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Objectives Mucolipidoses II and III alpha/beta (ML II and ML III) are lysosomal disorders in which the essential mannose-6-phosphate recognition marker is not synthesized onto lysosomal hydrolases and other glycoproteins. The disorders are caused by mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. Clinical, biochemical, and molecular findings in 61 probands (63 patients) are presented in order to provide a broad perspective of these mucolipidoses. Methods GNPTAB was sequenced in all probands and/or parents. Activity of several lysosomal enzymes was measured in plasma, and GlcNac-1-phosphotransferase was assayed in leukocytes. Thirty-six patients were studied in detail, allowing extensive clinical data to be abstracted. Results ML II correlates with near total absence of phosphotransferase activity resulting from homozygosity or compound heterozygosity for frameshift or nonsense mutations. Craniofacial and orthopedic manifestations are evident at birth, skeletal findings become more obvious within the first year, and growth is severely impaired. Speech, ambulation, and cognitive function are impaired. ML III retains a low level of phosphotransferase activity due to at least one missense or splice site mutation. The phenotype is milder with minimal delays in milestones, the appearance of facial coarsening by early school age, and slowing of growth after age four years. Conclusions Fifty-one pathogenic changes in GNPTAB are presented, including 42 novel mutations. Ample clinical information improves criteria for delineation of ML II and ML III. Phenotype-genotype correlations suggested in more general terms in earlier reports on smaller groups of patients are specified and extended.

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“…A second model of mucolipidosis II, GNPTAB-depleted zebrafish embryos, exhibits skeletal abnormalities, craniofacial defects and impaired motility allowed studies during early developmental stages and revealed changes in timing and expression of chondrogenic factors associated with altered chondrocyte differentiation and intracellular matrix homeostasis (Flanagan-Steet et al, 2009;Petrey et al, 2012). Recently, a Gnptab gene trap mouse model was described displaying elevated levels of serum acid hydrolases, reduced size, retinal degeneration and vacuolization in secretory epithelial cells of exocrine glands (Gelfman et al, 2007;Vogel et al, 2009). The mice, however, exhibited a relatively normal lifespan and failed to develop severe skeletal abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Lysosomal dysfunction causes neurodegeneration in mucolipidosis II ‘knock-in’ mice

Kollmann

Damme

Markmann

et al. 2012

Brain

104

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Mucolipidosis II is a neurometabolic lysosomal trafficking disorder of infancy caused by loss of mannose 6-phosphate targeting signals on lysosomal proteins, leading to lysosomal dysfunction and accumulation of non-degraded material. However, the identity of storage material and mechanisms of neurodegeneration in mucolipidosis II are unknown. We have generated 'knock-in' mice with a common mucolipidosis II patient mutation that show growth retardation, progressive brain atrophy, skeletal abnormalities, elevated lysosomal enzyme activities in serum, lysosomal storage in fibroblasts and brain and premature death, closely mimicking the mucolipidosis II disease in humans. The examination of affected mouse brains at different ages by immunohistochemistry, ultrastructural analysis, immunoblotting and mass spectrometric analyses of glycans and anionic lipids revealed that the expression and proteolytic processing of distinct lysosomal proteins such as α-l-fucosidase, β-hexosaminidase, α-mannosidase or Niemann-Pick C2 protein are more significantly impacted by the loss of mannose 6-phosphate residues than enzymes reaching lysosomes independently of this targeting mechanism. As a consequence, fucosylated N-glycans, GM2 and GM3 gangliosides, cholesterol and bis(monoacylglycero)phosphate accumulate progressively in the brain of mucolipidosis II mice. Prominent astrogliosis and the accumulation of organelles and storage material in focally swollen axons were observed in the cerebellum and were accompanied by a loss of Purkinje cells. Moreover, an increased neuronal level of the microtubule-associated protein 1 light chain 3 and the formation of p62-positive neuronal aggregates indicate an impairment of constitutive autophagy in the mucolipidosis II brain. Our findings demonstrate the essential role of mannose 6-phosphate for selected lysosomal proteins to maintain the capability for degradation of sequestered components in lysosomes and autophagolysosomes and prevent neurodegeneration. These lysosomal proteins might be a potential target for a valid therapeutic approach for mucolipidosis II disease.

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Comparative Pathology of Murine Mucolipidosis Types II and IIIC

Cited by 5 publications

References 13 publications

Disruption of the Man‐6‐P Targeting Pathway in Mice Impairs Osteoclast Secretory Lysosome Biogenesis

Disruption of the Man‐6‐P Targeting Pathway in Mice Impairs Osteoclast Secretory Lysosome Biogenesis

Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands

Lysosomal dysfunction causes neurodegeneration in mucolipidosis II ‘knock-in’ mice

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