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Impaired cargo clearance in the Retinal Pigment Epithelium (RPE) underlies irreversible blinding diseases

Impaired cargo clearance in the Retinal Pigment Epithelium (RPE) underlies irreversible blinding diseases
Impaired cargo clearance in the Retinal Pigment Epithelium (RPE) underlies irreversible blinding diseases
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.
Retinal Pigment Epithelium (RPE), endosomes, Phagosomes, Lysosomes, autophagy, RPE cultures, Age-related Macular Degeneration (AMD)
2073-4409
1-19
Ratnayaka, Janaka
002499b8-1a9f-45b6-9539-5ac145799dfd
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Tumbarello, David
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Ratnayaka, Janaka
002499b8-1a9f-45b6-9539-5ac145799dfd
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Tumbarello, David
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd

Ratnayaka, Janaka, Lotery, Andrew, Tumbarello, David and Ratnayaka, J. Arjuna (2018) Impaired cargo clearance in the Retinal Pigment Epithelium (RPE) underlies irreversible blinding diseases. Cells, 7 (2), 1-19. (doi:10.3390/cells7020016).

Record type: Article

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.

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Accepted/In Press date: 22 February 2018
e-pub ahead of print date: 23 February 2018
Published date: 2018
Keywords: Retinal Pigment Epithelium (RPE), endosomes, Phagosomes, Lysosomes, autophagy, RPE cultures, Age-related Macular Degeneration (AMD)

Identifiers

Local EPrints ID: 418316
URI: http://eprints.soton.ac.uk/id/eprint/418316
ISSN: 2073-4409
PURE UUID: 11c67de3-59fa-49fc-9b3e-01e5a73a72de
ORCID for Janaka Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for David Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938

Catalogue record

Date deposited: 28 Feb 2018 17:30
Last modified: 22 Nov 2021 03:06

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