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Cells 2018, 7(2), 16; https://doi.org/10.3390/cells7020016

Impaired Cargo Clearance in the Retinal Pigment Epithelium (RPE) Underlies Irreversible Blinding Diseases

1
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton SO16 6YD, UK
2
Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
3
Biological Sciences, Faculty of Natural & Environmental Sciences, Life Science Building 85, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK
*
Author to whom correspondence should be addressed.
Received: 28 January 2018 / Revised: 20 February 2018 / Accepted: 22 February 2018 / Published: 23 February 2018
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Abstract

Chronic degeneration of the Retinal Pigment Epithelium (RPE) is a precursor to pathological changes in the outer retina. The RPE monolayer, which lies beneath the neuroretina, daily internalises and digests large volumes of spent photoreceptor outer segments. Impaired cargo handling and processing in the endocytic/phagosome and autophagy pathways lead to the accumulation of lipofuscin and pyridinium bis-retinoid A2E aggregates and chemically modified compounds such as malondialdehyde and 4-hydroxynonenal within RPE. These contribute to increased proteolytic and oxidative stress, resulting in irreversible damage to post-mitotic RPE cells and development of blinding conditions such as age-related macular degeneration, Stargardt disease and choroideremia. Here, we review how impaired cargo handling in the RPE results in their dysfunction, discuss new findings from our laboratory and consider how newly discovered roles for lysosomes and the autophagy pathway could provide insights into retinopathies. Studies of these dynamic, molecular events have also been spurred on by recent advances in optics and imaging technology. Mechanisms underpinning lysosomal impairment in other degenerative conditions including storage disorders, α-synuclein pathologies and Alzheimer’s disease are also discussed. Collectively, these findings help transcend conventional understanding of these intracellular compartments as simple waste disposal bags to bring about a paradigm shift in the way lysosomes are perceived. View Full-Text
Keywords: Retinal Pigment Epithelium (RPE); endosomes; phagosomes; lysosomes; autophagy; RPE cultures; Age-related Macular Degeneration (AMD) Retinal Pigment Epithelium (RPE); endosomes; phagosomes; lysosomes; autophagy; RPE cultures; Age-related Macular Degeneration (AMD)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Keeling, E.; Lotery, A.J.; Tumbarello, D.A.; Ratnayaka, J.A. Impaired Cargo Clearance in the Retinal Pigment Epithelium (RPE) Underlies Irreversible Blinding Diseases. Cells 2018, 7, 16.

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