Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

Rakoczy, P. Elizabeth; Zhang, Dan; Robertson, Terry; Barnett, Nigel L.; Papadimitriou, John; Constable, Ian J.; Lai, Chooi-May

doi:10.1016/s0002-9440(10)64427-6

Cited by 157 publications

(122 citation statements)

References 42 publications

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“…Similar neuronal storage and death have been found in cathepsin D-deficient sheep (35). An increased photoreceptor cell death has also been noticed in a transgenic mouse model expressing an enzymatically inactive cathepsin D (36). Similarly, mice lacking cathepsins B and L display brain atrophy because of massive apoptosis of selected neurons in the cerebral cortex and the cerebellar Purkinje and granular cell layers (37).…”

supporting

confidence: 53%

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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supporting

confidence: 53%

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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“…48 Similar neuronal storage and death have been found in the cathepsin D-deficient sheep. 12 An increased photoreceptor cell death has also been noticed in a transgenic mouse model expressing an enzymatically inactive cathepsin D. 49 These observations strongly suggest that cathepsin D is essential for the proteolysis of proteins regulating cell growth and tissue homeostasis.…”

Section: Discussion Cathepsin D In Cell Deathmentioning

confidence: 96%

Stress-induced apoptosis is impaired in cells with a lysosomal targeting defect but is not affected in cells synthesizing a catalytically inactive cathepsin D

et al. 2003

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The role of cathepsin D in stress-induced cell death has been investigated by using ovine fibroblasts exhibiting a missense mutation in the active site of cathepsin D. The cathepsin D (lysosomal aspartic protease) deficiency did not protect cells against toxicity induced by doxorubicin and other cytotoxic agents, neither did it protect cells from caspase activation. Moreover, the cathepsin D inhibitor, pepstatin A, did not prevent stress-induced cell death in human fibroblasts or lymphoblasts. The possible role of lysosomal ceramide or sphingosine-mediated activation of cathepsin D in apoptosis was also excluded by using human cells either overexpressing or deficient in acid ceramidase. However, a normal lysosomal function seems to be required for efficient cell death, as indicated by the finding that fibroblasts from patients with mucolipidosis II were partially resistant to staurosporine, sphingosine and TNF-induced apoptosis, suggesting a key role of lysosomes in cell death.

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“…Digestion of the ROS within the RPE is also essential. Accumulation of undigested ROS material within the RPE, whether due to mutations in lysosomal proteases (Rakoczy et al 2002) or due to accumulation of natural non-degradative substrates (e.g. lipofuscin, Finnemann et al 2002), similarly causes photoreceptor cell death.…”

Section: Introductionmentioning

confidence: 99%

The unconventional myosin-VIIa associates with lysosomes

Soni

Warren

Bucci

et al. 2005

Cell Motil. Cytoskeleton

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Mutations in the myosin-VIIa (MYO7a) gene cause human Usher disease, characterized by hearing impairment and progressive retinal degeneration. In the retina, myosin-VIIa is highly expressed in the retinal pigment epithelium, where it plays a role in the positioning of melanosomes and other digestion organelles. Using a human cultured retinal pigmented epithelia cell line, ARPE-19, as a model system, we have found that a population of myosin-VIIa is associated with cathepsin D-and Rab7-positive lysosomes. Association of myosin-VIIa with lysosomes was Rab7 independent, as dominant negative and dominant active versions of Rab7 did not disrupt myosin-VIIa recruitment to lysosomes. Association of myosin-VIIa with lysosomes was also independent of the actin and microtubule cytoskeleton. Myosin-VIIa copurified with lysosomes on density gradients, and fractionation and extraction experiments suggested that it was tightly associated with the lysosome surface. These studies suggest that myosin-VIIa is a lysosome motor.

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Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

Abstract: Age-related macular degeneration (AMD), a disease of the area centralis or macula, is the leading cause of blindness in the elderly population of the developed world.

Cited by 157 publications

References 42 publications

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

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

Stress-induced apoptosis is impaired in cells with a lysosomal targeting defect but is not affected in cells synthesizing a catalytically inactive cathepsin D

The unconventional myosin-VIIa associates with lysosomes

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