{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:11:56Z","timestamp":1790784716753,"version":"4.1.0"},"reference-count":162,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,23]],"date-time":"2018-02-23T00:00:00Z","timestamp":1519344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Macular Society UK","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3R)","award":["# NC\/L001152\/1"],"award-info":[{"award-number":["# NC\/L001152\/1"]}]},{"name":"RP Fighting Blindness","award":["GR590"],"award-info":[{"award-number":["GR590"]}]},{"DOI":"10.13039\/501100000305","name":"National Eye Research Centre","doi-asserted-by":"publisher","award":["SAC 020"],"award-info":[{"award-number":["SAC 020"]}],"id":[{"id":"10.13039\/501100000305","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fight for Sight\/Alzheimer\u2019s Research UK","award":["Ref: 24AZ172"],"award-info":[{"award-number":["Ref: 24AZ172"]}]},{"name":"the Gift of Sight Appeal","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"AJL is a NIHR Senior Investigator","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"DAT is supported by a Wellcome Trust Seed Award","award":["205909\/Z\/17\/Z"],"award-info":[{"award-number":["205909\/Z\/17\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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, \u03b1-synuclein pathologies and Alzheimer\u2019s 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.<\/jats:p>","DOI":"10.3390\/cells7020016","type":"journal-article","created":{"date-parts":[[2018,2,23]],"date-time":"2018-02-23T11:20:29Z","timestamp":1519384829000},"page":"16","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Impaired Cargo Clearance in the Retinal Pigment Epithelium (RPE) Underlies Irreversible Blinding Diseases"],"prefix":"10.3390","volume":"7","author":[{"given":"Eloise","family":"Keeling","sequence":"first","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton SO16 6YD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Lotery","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton SO16 6YD, UK"},{"name":"Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5169-0561","authenticated-orcid":false,"given":"David","family":"Tumbarello","sequence":"additional","affiliation":[{"name":"Biological Sciences, Faculty of Natural &amp; Environmental Sciences, Life Science Building 85, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1027-6938","authenticated-orcid":false,"given":"J.","family":"Ratnayaka","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP806, Tremona Road, Southampton SO16 6YD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1152\/physiol.00038.2009","article-title":"Phagocytosis of retinal rod and cone photoreceptors","volume":"25","author":"Kevany","year":"2010","journal-title":"Physiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1083\/jcb.49.2.303","article-title":"The renewal of rod and cone outer segments in the rhesus monkey","volume":"49","author":"Young","year":"1971","journal-title":"J. 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