{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:58:27Z","timestamp":1783997907314,"version":"3.55.0"},"reference-count":64,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY025002"],"award-info":[{"award-number":["EY025002"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY007026"],"award-info":[{"award-number":["EY007026"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY000331"],"award-info":[{"award-number":["EY000331"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008623","name":"Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008623","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2024,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Recessive Stargardt disease (STGD1) is an inherited juvenile maculopathy caused by mutations in the\n                    <jats:italic>ABCA4<\/jats:italic>\n                    gene, for which there is no suitable treatment. Loss of functional ABCA4 in the retinal pigment epithelium (RPE) alone, without contribution from photoreceptor cells, was shown to induce STGD1 pathology. Here, we identified cathepsin D (CatD), the primary RPE lysosomal protease, as a key molecular player contributing to endo\u2010lysosomal dysfunction in STGD1 using a newly developed \u201cdisease\u2010in\u2010a\u2010dish\u201d RPE model from confirmed STGD1 patients. Induced pluripotent stem cell (iPSC)\u2010derived RPE originating from three STGD1 patients exhibited elevated lysosomal pH, as previously reported in\n                    <jats:italic>Abca4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. CatD protein maturation and activity were impaired in RPE from STGD1 patients and\n                    <jats:italic>Abca4<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Consequently, STGD1 RPE cells have reduced photoreceptor outer segment degradation and abnormal accumulation of \u03b1\u2010synuclein, the natural substrate of CatD. Furthermore, dysfunctional ABCA4 in STGD1 RPE cells results in intracellular accumulation of autofluorescent material and phosphatidylethanolamine (PE). The altered distribution of PE associated with the internal membranes of STGD1 RPE cells presumably compromises LC3\u2010associated phagocytosis, contributing to delayed endo\u2010lysosomal degradation activity. Drug\u2010mediated re\u2010acidification of lysosomes in the RPE of STGD1 restores CatD functional activity and reduces the accumulation of immature CatD protein loads. This preclinical study validates the contribution of CatD deficiencies to STGD1 pathology and provides evidence for an efficacious therapeutic approach targeting RPE cells. Our findings support a cell\u2010autonomous RPE\u2010driven pathology, informing future research aimed at targeting RPE cells to treat ABCA4\u2010mediated retinopathies.\n                  <\/jats:p>","DOI":"10.1096\/fj.202400210rr","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T13:01:54Z","timestamp":1717592514000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Impaired cathepsin D in retinal pigment epithelium cells mediates Stargardt disease pathogenesis"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-3187","authenticated-orcid":false,"given":"Eunice Sze Yin","family":"Ng","sequence":"first","affiliation":[{"name":"UCLA Stein Eye Institute University of California  Los Angeles California USA"},{"name":"Department of Ophthalmology, David Geffen School of Medicine University of California  Los Angeles California USA"},{"name":"Molecular, Cellular, and Integrative Physiology Interdepartmental Program University of California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Hu","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute University of California  Los Angeles California USA"},{"name":"Department of Ophthalmology, David Geffen School of Medicine University of California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichun","family":"Jiang","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute University of California  Los Angeles California USA"},{"name":"Department of Ophthalmology, David Geffen School of Medicine University of California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-6403","authenticated-orcid":false,"given":"Roxana A.","family":"Radu","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute University of California  Los Angeles California USA"},{"name":"Department of Ophthalmology, David Geffen School of Medicine University of California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"issue":"10","key":"e_1_2_10_2_1","first-page":"2229","article-title":"Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone\u2010rod degeneration","volume":"42","author":"Briggs CE","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12081241"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2021.101036"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5333.1805"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/303079"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-13624"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80602-9"},{"issue":"8","key":"e_1_2_10_9_1","first-page":"1685","article-title":"Delayed dark\u2010adaptation and lipofuscin accumulation in abcr+\/\u2212 mice: implications for involvement of ABCR in age\u2010related macular degeneration","volume":"42","author":"Mata NL","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh048"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0185-4"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.05.004"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.982063"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.1993.supplement_17.27"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4835(80)90112-8"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.62.9.39"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64427-6"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a131034"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-0719-9_17"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.08.099"},{"issue":"3","key":"e_1_2_10_21_1","first-page":"737","article-title":"Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin","volume":"40","author":"Holz FG","year":"1999","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-0675"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1167\/tvst.11.3.33"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00242"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11213462"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711983105"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60327-325-1_2"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-1470"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0076-6879(00)16731-x"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1139\/o59-099"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2020.100235"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7720-8_4"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2014.05.013"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071679"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21394"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi800699v"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24182"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.581805"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.42.2.392"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00021.2004"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.06.012"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-014-8920-5"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3192"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-75402-4_74"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620299114"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1927"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201500127"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802519115"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2014.01.001"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.19-27241"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12952"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9488-5_14"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2022.10.001"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/4829180"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.1c08044"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.0030220"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.185702"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.117.2.301"},{"issue":"6","key":"e_1_2_10_59_1","first-page":"1179","article-title":"An analysis of allelic variation in the ABCA4 gene","volume":"42","author":"Webster AR","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq284"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129462"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1520335113"},{"key":"e_1_2_10_63_1","volume-title":"Handbook of Proteolytic Enzymes","author":"Barrett AJ","year":"2004"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-05-1028"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01131"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202400210RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T22:15:47Z","timestamp":1761689747000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202400210RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":64,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,6,15]]}},"alternative-id":["10.1096\/fj.202400210RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202400210rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,5]]},"assertion":[{"value":"2024-01-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e23720"}}