{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:55:58Z","timestamp":1787655358917,"version":"build-2736575974"},"reference-count":77,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2018,7,19]],"date-time":"2018-07-19T00:00:00Z","timestamp":1531958400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"crossref","award":["01GQ1422B"],"award-info":[{"award-number":["01GQ1422B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"crossref","award":["031A535A"],"award-info":[{"award-number":["031A535A"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"\n Background<\/jats:title>\n \n Stargardt disease (SD) is characterized by the accumulation of the age-pigment lipofuscin in the retinal pigment epithelium (RPE) and subsequent neuroretinal degeneration. The disease leads to vision loss early in life. Here, we investigate age-dependent ultrastructural changes in three SD mouse models: albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n and pigmented\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n and\n \n Abca4\n -\/-<\/jats:sup>\n .Rdh8\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice. Since we found indications for oxidative stress primarily in albino SD mice, we tested RPE melanin for its antioxidative capabilities.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n SD mouse eyes were investigated by light, fluorescence and electron microscopy and were compared to the respective albino and pigmented wild type mice and to a human donor SD eye. To confirm the role of RPE melanin in scavenging oxidative stress, melanin from\n S. officinalis<\/jats:italic>\n as a standard and porcine RPE were tested for their capability to quench superoxide anions.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Histological alterations indicative of oxidative stress and\/or lysosomal dysfunction were present in albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n and\n \n Abca4\n -\/-<\/jats:sup>\n .Rdh8\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice. Retinal damage, such as inner segment rupture and pyknotic or free photoreceptor nuclei in the subretinal space and RPE vacuolization were exclusively found in albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice. Shortened and disorganized photoreceptor outer segments and dead RPE cells were found in albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n and\n \n Abca4\n -\/-<\/jats:sup>\n .Rdh8\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice, with earlier onset in albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice. Undegraded phagosomes and lipofuscin accumulation were present in the RPE of all three SD strains, but numbers were highest in\n \n Abca4\n -\/-<\/jats:sup>\n .Rdh8\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice. Lipofuscin morphology differed between SD strains: (melano-)lipofuscin granules in pigmented\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice had a homogenous electron density and sharp demarcations, while lipofuscin in albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice had a flocculent electron density and often lacked a surrounding membrane, indicating loss of lysosomal integrity. Young\n \n Abca4\n -\/-<\/jats:sup>\n .Rdh8\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice showed (melano-)lipofuscin granules with homogenous electron density, while in aged animals granules with flocculent electron density predominated. Both strains of pigmented SD mice had melanolipofuscin clusters as found in the human SD eye. Like melanin from\n S. officinalis<\/jats:italic>\n , porcine RPE melanin can also quench superoxide anions.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n The presented pathologies in albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n and\n \n Abca4\n -\/-<\/jats:sup>\n .Rdh8\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice suggest oxidative stress and\/or lysosomal dysfunction within the RPE. Since albino\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice have the earliest onset and severest damage and as absence of melanin and also melanin turnover with age are known to diminish RPEs anti-oxidative properties, we assume that RPE melanin plays a role in SD related damages. A lack of pathology in pigmented\n \n Abca4\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice due to lower stress levels as compared to the\n \n Abca4\n -\/-<\/jats:sup>\n .Rdh8\n -\/-<\/jats:sup>\n <\/jats:italic>\n mice underlines this hypothesis. It is also supported by the finding that RPE melanin can quench superoxide anions. We therefore suppose that RPE melanin is important in retinal health and we discuss its role as an oxidative stress scavenger.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.7717\/peerj.5215","type":"journal-article","created":{"date-parts":[[2018,7,19]],"date-time":"2018-07-19T03:12:01Z","timestamp":1531969921000},"page":"e5215","source":"Crossref","is-referenced-by-count":50,"title":["Ultrastructural alterations in the retinal pigment epithelium and photoreceptors of a Stargardt patient and three Stargardt mouse models: indication for the central role of RPE melanin in oxidative stress"],"prefix":"10.7717","volume":"6","author":[{"given":"Tatjana","family":"Taubitz","sequence":"first","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Tschulakow","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Tikhonovich","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Illing","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Biesemeier","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Julien-Schraermeyer","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Schraermeyer","sequence":"additional","affiliation":[{"name":"Division of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4443","published-online":{"date-parts":[[2018,7,19]]},"reference":[{"key":"10.7717\/peerj.5215\/ref-1","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1038\/ng0397-236","article-title":"A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy","volume":"15","author":"Allikmets","year":"1997","journal-title":"Nature Genetics"},{"key":"10.7717\/peerj.5215\/ref-2","doi-asserted-by":"publisher","first-page":"2424","DOI":"10.1093\/bioinformatics\/btx180","article-title":"Trainable weka segmentation: a machine learning tool for microscopy pixel classification","volume":"33","author":"Arganda-Carreras","year":"2017","journal-title":"Bioinformatics"},{"key":"10.7717\/peerj.5215\/ref-3","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1006\/excr.1994.1157","article-title":"Superoxide inhibits proliferation and phagocytic internalization of photoreceptor outer segments by bovine retinal pigment epithelium in vitro","volume":"212","author":"Becquet","year":"1994","journal-title":"Experimental Cell Research"},{"key":"10.7717\/peerj.5215\/ref-4","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1002\/1521-3773(20020301)41:5%3C814::AID-ANIE814%3E3.0.CO;2-2","article-title":"Formation of a nonaoxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement","volume":"41","author":"Ben-Shabat","year":"2002","journal-title":"Angewandte Chemie International Edition in English"},{"key":"10.7717\/peerj.5215\/ref-5","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.jphotobiol.2007.11.005","article-title":"UV-A induced oxidative stress is more prominent in naturally pigmented aged human RPE cells compared to non-pigmented human RPE cells independent of zinc treatment","volume":"90","author":"Biesemeier","year":"2008","journal-title":"Journal of Photochemistry and Photobiology. 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