Inhibition of Lysosomal Degradation in Retinal Pigment Epithelium Cells Induces Exocytosis of Phagocytic Residual Material at the Basolateral Plasma Membrane

Peters, Swaantje; Reinthal, Eva; Blitgen-Heinecke, Petra; Bartz-Schmidt, Karl-Ulrich; Schraermeyer, Ulrich

doi:10.1159/000090268

Cited by 37 publications

(32 citation statements)

References 24 publications

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“…Chronic treatment of rats with chloroquine leads to the accumulation of lysosomal-associated organelles and multilamellar bodies within the RPE cells [18, 19]. Of particular relevance is the accumulation of partially degraded material of photoreceptor origin in and around Bruch’s membrane.…”

Section: 3 Consequences Of Lysosomal Alkalinization On Degradationmentioning

confidence: 99%

Rescue of Compromised Lysosomes Enhances Degradation of Photoreceptor Outer Segments and Reduces Lipofuscin-Like Autofluorescence in Retinal Pigmented Epithelial Cells

Guha

Baltazar

et al. 2014

Advances in Experimental Medicine and Biology

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Healthful cell maintenance requires the efficient degradative processing and removal of waste material. Retinal pigmented epithelial (RPE) cells have the onerous task of degrading both internal cellular debris generated through autophagy as well as phagocytosed photoreceptor outer segments. We propose that the inadequate processing material with the resulting accumulation of cellular waste contributes to the downstream pathologies characterized as age-related macular degeneration (AMD). The lysosomal enzymes responsible for clearance function optimally over a narrow range of acidic pH values; elevation of lysosomal pH by compounds like chloroquine or A2E can impair degradative enzyme activity and lead to a lipofuscin-like autofluorescence. Restoring acidity to the lysosomes of RPE cells can enhance activity of multiple degradative enzymes and is therefore a logical target in early AMD. We have identified several approaches to reacidify lysosomes of compromised RPE cells; stimulation of beta-adrenergic, A2A adenosine and D5 dopamine receptors each lowers lysosomal pH and improves degradation of photoreceptor outer segments. Activation of the CFTR chloride channel also reacidifies lysosomes and increases degradation. These approaches also restore the lysosomal pH of RPE cells from aged ABCA4−/− mice with chronically high levels of A2E, suggesting that functional signaling pathways to reacidify lysosomes are retained in aged cells like those in patients with AMD. Acidic nanoparticles transported to RPE lysosomes also lower pH and improve degradation of outer segments. In summary, the ability of diverse approaches to lower lysosomal pH and enhance outer segment degradation support the proposal that lysosomal acidification can prevent the accumulation of lipofuscin-like material in RPE cells.

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Section: 3 Consequences Of Lysosomal Alkalinization On Degradationmentioning

confidence: 99%

Rescue of Compromised Lysosomes Enhances Degradation of Photoreceptor Outer Segments and Reduces Lipofuscin-Like Autofluorescence in Retinal Pigmented Epithelial Cells

Guha

Baltazar

et al. 2014

Advances in Experimental Medicine and Biology

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“…62,63 However, changes in lysosomal pH alone can mimic pathology in the diseased eye, with chloroquine treatment leading to the accumulation of material on Bruch membrane. 15 Combined with the alkalinizing effects of chronic A2E exposure, this suggests that lowering lysosomal pH may be beneficial when pathologic levels of undigested material accumulate in the RPE and Bruch membrane.…”

Section: Implications For Rpe Healthmentioning

confidence: 99%

“…13,14 Chloroquine treatment also led to the accumulation of material on Bruch membrane. 15 Tamoxifen can alkalinize lysosomes, and tamoxifen decreased activity of cathepsin D in RPE cells. 16,17 The potential for N-retinylidene-N-retinylethanolamine (A2E) to alter lysosomal pH may be particularly relevant because A2E is increased in the RPE of patients with Stargardt disease and in the ABCA4 Ϫ/Ϫ mouse model of the disease.…”

mentioning

confidence: 99%

Restoration of Lysosomal pH in RPE Cells from Cultured Human and ABCA4^−/−Mice: Pharmacologic Approaches and Functional Recovery

Liu¹,

Lu²,

Reigada³

et al. 2008

Invest. Ophthalmol. Vis. Sci.

126

161

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“…Administration of the lysosmotic compound chloroquine leads to the incomplete digestion of photoreceptor outer segments within RPE cells, an increase in lysosomal-associated organelles, and the accumulation of extracellular debris around adjacent Bruch's membrane and choriocapillaris (24,29). Similarly, tamoxifen raises lysosomal pH and slows outer segment clearance in RPE cells (20).…”

mentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator contributes to reacidification of alkalinized lysosomes in RPE cells

Liu

Guha

et al. 2012

American Journal of Physiology-Cell Physiology

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The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in lysosomal acidification has been difficult to determine. We demonstrate here that CFTR contributes more to the reacidification of lysosomes from an elevated pH than to baseline pH maintenance. Lysosomal alkalinization is increasingly recognized as a factor in diseases of accumulation, and we previously showed that cAMP reacidified alkalinized lysosomes in retinal pigmented epithelial (RPE) cells. As the influx of anions to electrically balance proton accumulation may enhance lysosomal acidification, the contribution of the cAMP-activated anion channel CFTR to lysosomal reacidification was probed. The antagonist CFTR(inh)-172 had little effect on baseline levels of lysosomal pH in cultured human RPE cells but substantially reduced the reacidification of compromised lysosomes by cAMP. Likewise, CFTR activators had a bigger impact on cells whose lysosomes had been alkalinized. Knockdown of CFTR with small interfering RNA had a larger effect on alkalinized lysosomes than on baseline levels. Inhibition of CFTR in isolated lysosomes altered pH. While CFTR and Lamp1 were colocalized, treatment with cAMP did not increase targeting of CFTR to the lysosome. The inhibition of CFTR slowed lysosomal degradation of photoreceptor outer segments while activation of CFTR enhanced their clearance from compromised lysosomes. Activation of CFTR acidified RPE lysosomes from the ABCA4(-/-) mouse model of recessive Stargardt's disease, whose lysosomes are considerably alkalinized. In summary, CFTR contributes more to reducing lysosomal pH from alkalinized levels than to maintaining baseline pH. Treatment to activate CFTR may thus be of benefit in disorders of accumulation associated with lysosomal alkalinization.

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Inhibition of Lysosomal Degradation in Retinal Pigment Epithelium Cells Induces Exocytosis of Phagocytic Residual Material at the Basolateral Plasma Membrane

Cited by 37 publications

References 24 publications

Rescue of Compromised Lysosomes Enhances Degradation of Photoreceptor Outer Segments and Reduces Lipofuscin-Like Autofluorescence in Retinal Pigmented Epithelial Cells

Rescue of Compromised Lysosomes Enhances Degradation of Photoreceptor Outer Segments and Reduces Lipofuscin-Like Autofluorescence in Retinal Pigmented Epithelial Cells

Restoration of Lysosomal pH in RPE Cells from Cultured Human and ABCA4^−/−Mice: Pharmacologic Approaches and Functional Recovery

Cystic fibrosis transmembrane conductance regulator contributes to reacidification of alkalinized lysosomes in RPE cells

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Inhibition of Lysosomal Degradation in Retinal Pigment Epithelium Cells Induces Exocytosis of Phagocytic Residual Material at the Basolateral Plasma Membrane

Cited by 37 publications

References 24 publications

Rescue of Compromised Lysosomes Enhances Degradation of Photoreceptor Outer Segments and Reduces Lipofuscin-Like Autofluorescence in Retinal Pigmented Epithelial Cells

Rescue of Compromised Lysosomes Enhances Degradation of Photoreceptor Outer Segments and Reduces Lipofuscin-Like Autofluorescence in Retinal Pigmented Epithelial Cells

Restoration of Lysosomal pH in RPE Cells from Cultured Human and ABCA4−/−Mice: Pharmacologic Approaches and Functional Recovery

Cystic fibrosis transmembrane conductance regulator contributes to reacidification of alkalinized lysosomes in RPE cells

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Restoration of Lysosomal pH in RPE Cells from Cultured Human and ABCA4^−/−Mice: Pharmacologic Approaches and Functional Recovery