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Dittmer, Frank; Hafner, A.; Ulbrich, Eva; Moritz, J.; Schmidt, P; Schmahl, Wolfgang W.; Pohlmann, R; Figura, Kurt Von

doi:10.1023/a:1008823315416

Cited by 27 publications

(11 citation statements)

References 25 publications

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“…The MPRs are responsible for the recruitment of the majority of AP-1 complexes to the TGN (35), and they serve as receptors for soluble lysosomal enzymes and insulin-like growth factor II. Mice lacking both MPRs are viable albeit at a reduced rate (36,37), and embryonic development is normal in I-cell disease (38), in which M6P-containing ligands are missorted because of the absence of the M6P recognition marker. AP-1 could be important for prohormone processing and secretion of proteins critical for embryonic development.…”

Section: Discussionmentioning

confidence: 99%

Early Embryonic Death of Mice Deficient in γ-Adaptin

Zizioli¹,

Meyer²,

Guhde³

et al. 1999

Journal of Biological Chemistry

132

125

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Intracellular protein transport and sorting by vesicles in the secretory and endocytic pathways requires the formation of a protein coat on the membrane. The heterotetrameric adaptor protein complex 1 (AP-1) promotes the formation of clathrin-coated vesicles at the trans-Golgi network. AP-1 interacts with various sorting signals in the cytoplasmic tails of cargo molecules, thus indicating a function in protein sorting. We generated mutants of the ␥-adaptin subunit of AP-1 in mice to investigate its role in post-Golgi vesicle transport and sorting processes. ␥-Adaptin-deficient embryos develop until day 3.5 post coitus and die during the prenidation period, revealing that AP-1 is essential for viability. In heterozygous mice the amount of AP-1 complexes is reduced to half of controls. Free ␤1-or 1 chains were not detectable, indicating that they are unstable unless they are part of AP-1 complexes. Heterozygous mice weigh less then their wild-type littermates and show impaired T cell development.At several sites along the secretory and the endocytic routes the transport of membrane proteins and luminal cargo depends on the formation of carrier vesicles. The formation of these transport vesicles is facilitated by coat proteins. Budding from the Golgi and endoplasmic reticulum membranes involves the heptameric COP-I and COP-II complexes. Budding from the trans-Golgi network (TGN), 1 the plasma membrane, and also probably from membranes of the endosomal/lysosomal system involves heterotetrameric adaptor protein (AP) complexes of which three types are known at present and which show homology to the COP-I subunits (1-3).AP-1 and AP-2 have been implicated in the formation of clathrin-coated vesicles at the TGN and the plasma membrane, respectively, but may participate also in vesicle formation at other sites (3-5). AP-3-mediated vesicle formation may take place at the TGN and/or endosomes (6 -8).Although most of our knowledge on AP function is derived from studies on their subcellular localization and interaction with membranes or cytoplasmic domains of membrane proteins, little is based on in vivo functional studies or genetic approaches. Deletion of genes of AP subunits in yeast did not reveal the function of AP-1 and AP-2 but was informative in the case of AP-3. Mutations of the four AP-1 and AP-2 subunits did not result in a mutant phenotype and only the combination of AP-1 mutations with a temperature-sensitive clathrin heavychain mutation enhanced the reduced growth rate observed in the clathrin heavy-chain mutant (9 -11). 2 No biochemical data for cargo-AP-1 interactions are available in the yeast system. The AP-3 is needed for an alternative pathway from the TGN to the vacuole, which is utilized by the vacuolar alkaline phosphatase and the vacuolar t-SNARE Vam3p and does not depend on clathrin (12). In Drosophila melanogaster AP-3 is involved in the formation of pigment granules, as indicated by garnet, an eye color mutant caused by mutations in one of the AP-3 subunits (8, 13). Further support for a role of AP-...

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Section: Discussionmentioning

confidence: 99%

Early Embryonic Death of Mice Deficient in γ-Adaptin

Zizioli¹,

Meyer²,

Guhde³

et al. 1999

Journal of Biological Chemistry

132

125

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“…Indeed, deficiency of MPRs in triple-deficient fibroblasts results in abundant secretion of M6P-containing lysosomal enzymes in the culture medium (46). In this medium, the activities of two lysosomal enzymes, ␤-hexosaminidase and ␤-galactosidase, were dramatically increased, as compared with the medium of wild-type murine cells (Fig.…”

Section: Correction Of the Lysosomal Enzymatic Defect Of I-cell Diseamentioning

confidence: 90%

“…Murine fibroblasts derived from MPR46-deficient, MPR300-deficient (49), or triple-deficient mice (null alleles for Igf2, Mpr300, and Mpr46) (45) were kindly provided by Dr. K. von Figura (Göttingen, Germany). These cells were grown in a humidified 5% CO 2 atmosphere at 37°C in DMEM containing Glutamax (2 mM), penicillin (100 units/ml), strepto-FIG.…”

Section: Methodsmentioning

confidence: 99%

“…We then analyzed the response to TNF of fibroblasts derived from triple-deficient mice nullizygous for Igf2 and the two MPRs, Mpr300, Mpr46, which develop a phenotype that mimics the morphological and biochemical alterations characteristic of ICD (45). As compared with control murine cells, tripledeficient fibroblasts were dose-dependently resistant to TNF (Fig.…”

Section: I-cell Disease Fibroblasts Are Partially Resistant To Tnfmentioning

confidence: 99%

“…This results in gross cellular deficiencies of most lysosomal enzymes and is associated with severe clinical manifestations in the first few years of life (43). Clinical, biochemical, and morphological similarities between human ICD, and two conditions in animals have been reported, including in a cat (44) and in triple-deficient mice nullizygous for Igf2 and the two MPRs, Mpr300 and Mpr46 (45,46).…”

mentioning

confidence: 99%

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Mannose 6-Phosphorylated Proteins Are Required for Tumor Necrosis Factor-induced Apoptosis

Tardy¹,

Autefage

Garcia

et al. 2004

Journal of Biological Chemistry

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Whereas caspases are essential components in apoptosis, other proteases seem to be involved in programmed cell death. This study investigated the role of lysosomal mannose 6-phosphorylated proteins in tumor necrosis factor (TNF)-induced apoptosis. We report that fibroblasts isolated from patients affected with inclusion-cell disease (ICD), having a deficient activity of almost all lysosomal hydrolases, are resistant to the toxic effect of TNF. These mutant cells exhibited a defect in TNF-induced caspase activation, Bid cleavage, and release of cytochrome c. In contrast, TNF-induced p42/ p44 MAPK activation and CD54 expression remained unaltered. Human ICD lymphoblasts and fibroblasts derived from mice nullizygous for Igf2 and the two mannose 6-phosphate (M6P) receptors, Mpr300 and Mpr46, which develop an ICD-like phenotype, were also resistant to CD95 ligand and TNF, respectively. Moreover, correction of the lysosomal enzyme defect of ICD fibroblasts, using a medium enriched in M6P-containing proteins, enabled restoration of sensitivity to TNF. This effect was blocked by exogenous M6P but not by cathepsin B or L inhibitors. Altogether, these findings suggest that some M6P-bearing glycoproteins modulate the susceptibility to TNF-induced apoptosis. As a matter of fact, exogenous tripeptidyl peptidase 1, a lysosomal carboxypeptidase, could sensitize ICD fibroblasts to TNF. These observations highlight the hitherto unrecognized role of some mannose 6-phosphorylated proteins such as tripeptidyl peptidase 1 in the apoptotic cascade triggered by TNF.

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Gene therapy for lysosomal storage diseases: the lessons and promise of animal models

Ellinwood

Vite

Haskins

2004

The Journal of Gene Medicine

116

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There are more than 40 different forms of inherited lysosomal storage diseases (LSDs) known to occur in humans and the aggregate incidence has been estimated to approach 1 in 7000 live births. Most LSDs are associated with high morbidity and mortality and represent a significant burden on patients, their families, and health care providers. Except for symptomatic therapies, many LSDs remain untreatable, and gene therapy is among the only viable treatment options potentially available. Therapies for some LSDs do exist, or are under evaluation, including heterologous bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and substrate reduction therapy (SRT), but these treatment options are associated with significant concerns, including high morbidity and mortality (BMT), limited positive outcomes (BMT), incomplete response to therapy (BMT, ERT, and SRT), life-long therapy (ERT, SRT), and cost (BMT, ERT, SRT). Gene therapy represents a potential alternative therapy, albeit a therapy with its own attendant concerns. Animal models of LSDs play a critical role in evaluating the efficacy and safety of therapy for many of these conditions. Naturally occurring animal homologs of LSDs have been described in the mouse, rat, dog, cat, guinea pig, emu, quail, goat, cattle, sheep, and pig. In this review we discuss those animal models that have been used in gene therapy experiments and those with promise for future evaluations.

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Untitled

Cited by 27 publications

References 25 publications

Early Embryonic Death of Mice Deficient in γ-Adaptin

Early Embryonic Death of Mice Deficient in γ-Adaptin

Mannose 6-Phosphorylated Proteins Are Required for Tumor Necrosis Factor-induced Apoptosis

Gene therapy for lysosomal storage diseases: the lessons and promise of animal models

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