{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:04:31Z","timestamp":1784898271465,"version":"3.55.0"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008664","name":"Ono Medical Research Foundation","doi-asserted-by":"crossref","award":["Grant"],"award-info":[{"award-number":["Grant"]}],"id":[{"id":"10.13039\/501100008664","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"crossref","award":["Grant"],"award-info":[{"award-number":["Grant"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Japan National Society for the Prevention of Blindness","award":["Grant"],"award-info":[{"award-number":["Grant"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["Grant-in-Aid for Young Scientists,20K18341"],"award-info":[{"award-number":["Grant-in-Aid for Young Scientists,20K18341"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JST","award":["ERATO \u201cArita Lipidome Atlas Project\u201d (JPMJER2101"],"award-info":[{"award-number":["ERATO \u201cArita Lipidome Atlas Project\u201d (JPMJER2101"]}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","award":["Leading Initiative for Excellent Young Researchers (LEADER) program"],"award-info":[{"award-number":["Leading Initiative for Excellent Young Researchers (LEADER) program"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["Program for Intractable Diseases Research utilizing disease-specific iPS cells,15652070"],"award-info":[{"award-number":["Program for Intractable Diseases Research utilizing disease-specific iPS cells,15652070"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science London","doi-asserted-by":"crossref","award":["KAKENHI,16K11285,19K09991,15H05897,15H05898,20H00495,25K12831"],"award-info":[{"award-number":["KAKENHI,16K11285,19K09991,15H05897,15H05898,20H00495,25K12831"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,22]]},"abstract":"<jats:p>\n                    Malattia Leventinese (MAL) is an inherited macular degeneration disorder characterized by retinal drusen formation in adolescence, leading to vision loss. A mutation in the fibulin-3 gene (\n                    <jats:italic>EFEMP1<\/jats:italic>\n                    ) causes MAL; however, the mechanisms underlying disease onset and drusen formation remain unclear. In this study, we generated induced pluripotent stem cell\u2013derived retinal pigment epithelial (iPSC-RPE) cells from a patient with MAL to investigate disease mechanisms and potential therapies. MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis. Long-term culture with photoreceptor outer segments led to drusen-like deposits containing ApoE, complement components, and collagen IV accumulation, and it showed activation of matrix metalloproteinase-2 (MMP2). Untargeted lipid analysis revealed increased hexosylceramide and bis-monoacylglycerophosphate levels in MAL iPSC-RPE cells. A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels. Treatment with trehalose, a lysosome-modulating compound, increased lysosomal content and function, reducing drusen-like deposit formation, inhibiting MMP2 activation, and suppressing apoptosis. This study highlighted lysosomal dysfunction as a contributor to RPE damage, drusen-like deposit accumulation, and extracellular matrix degradation. Pharmacological restoration of lysosomal function alleviated these defects, suggesting therapeutic potential for MAL and other drusen-related diseases, including age-related macular degeneration.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.194102","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T18:01:12Z","timestamp":1784656872000},"source":"Crossref","is-referenced-by-count":0,"title":["Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese"],"prefix":"10.1172","volume":"11","author":[{"given":"Yumi","family":"Inoue","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanako O.","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan."},{"name":"Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7472-6002","authenticated-orcid":true,"given":"Yuto","family":"Iida","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Okamoto-Furuta","sequence":"additional","affiliation":[{"name":"Division of Electron Microscopic Study, Center for Anatomical Studies, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Asaka","sequence":"additional","affiliation":[{"name":"Department of Fundamental Cell Technology, Center for iPS Cell Research and Application (CiRA), Kyoto University, Sakyo-ku, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9902-0463","authenticated-orcid":true,"given":"Makoto","family":"Arita","sequence":"additional","affiliation":[{"name":"Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan."},{"name":"Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akitaka","family":"Tsujikawa","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.10.036"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2019.09.024"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31550-2"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010329"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1006\/exer.2001.1094"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.1973.01000050208006"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/9722"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0070"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.202491599"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4096"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm198"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm199"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx392"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.04.006"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.10-5984"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.147.7.1533"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nri2303"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.14.7.835"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1021\/bi00404a024"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.09.036"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.669168"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.06.001"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.1174447"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899753"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200109030"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12524"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nrm973"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14338"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1050"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1717338115"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710430114"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.32"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201593428"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40856"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50500-z"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11262-1"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033341"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1293"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/7651_2021_418"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2021.108503"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0531-2"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/194102\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:34:04Z","timestamp":1784896444000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/194102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":41,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7,22]]},"published-print":{"date-parts":[[2026,7,22]]}},"alternative-id":["10.1172\/jci.insight.194102"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.194102","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]},"article-number":"e194102"}}