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

Cells
Eloise KeelingJ Arjuna Ratnayaka

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-synu...Continue Reading

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Citations

Nov 23, 2019·International Journal of Molecular Sciences·Juha M T HyttinenKai Kaarniranta
Oct 2, 2019·International Journal of Molecular Sciences·Oyuna S KozhevnikovaNataliya G Kolosova
Jun 9, 2020·Oxidative Medicine and Cellular Longevity·Yuanzhong ZhangXinrong Xu
Aug 25, 2020·Oxidative Medicine and Cellular Longevity·Zi-Yuan ZhangGuang-Yu Li
Oct 3, 2018·F1000Research·Savannah A LynnJ Arjuna Ratnayaka
Mar 21, 2020·Frontiers in Cell and Developmental Biology·Daniela IntartagliaNicolina Cristina Sorrentino
Sep 17, 2020·International Journal of Molecular Sciences·Eloise KeelingJ Arjuna Ratnayaka
Aug 15, 2019·Scientific Reports·Nemanja MilićevićMarie-Paule Felder-Schmittbuhl
Feb 17, 2021·Investigative Ophthalmology & Visual Science·Fanfei LiuLawrence J Rizzolo
Nov 14, 2020·International Journal of Molecular Sciences·Eloise KeelingJ Arjuna Ratnayaka
Dec 8, 2020·Journal of Photochemistry and Photobiology. B, Biology·Ming JinXu Zhang
May 17, 2021·The FEBS Journal·Daniela IntartagliaIvan Conte
Jul 28, 2021·Investigative Ophthalmology & Visual Science·Cristina EscreventeMiguel C Seabra

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Methods Mentioned

BETA
GTPases
GTPase
glycosylation
MDA
imaging technology

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