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Formation of lipofuscin-like autofluorescent granules in the retinal pigment epithelium requires lysosome dysfunction

2021-07Artigo científico Acesso aberto
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dc.contributor.authorEscrevente, Cristina
dc.contributor.authorFalcão, Ana S.
dc.contributor.authorHall, Michael J.
dc.contributor.authorLopes-Da-Silva, Mafalda
dc.contributor.authorAntas, Pedro
dc.contributor.authorMesquita, Miguel M.
dc.contributor.authorFerreira, Inês S.
dc.contributor.authorHelena Cardoso, M.
dc.contributor.authorOliveira, Daniela
dc.contributor.authorFradinho, Ana C.
dc.contributor.authorCiossek, Thomas
dc.contributor.authorNicklin, Paul
dc.contributor.authorFutter, Clare E.
dc.contributor.authorTenreiro, Sandra
dc.contributor.authorSeabra, Miguel C.
dc.contributor.authorC Seabra, Miguel
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.institutioniNOVA4Health - pólo NMS
dc.contributor.pblAssociation for Research in Vision and Ophthalmology Inc.
dc.date.accessioned2021-10-22T03:42:48Z
dc.date.available2021-10-22T03:42:48Z
dc.date.issued2021-07
dc.descriptionFunding Information: Supported by Funda??o para a Ciência e Tecnologia (FCT) ? Portugal co-funded by FEDER under the PT2020 Partnership Agreement (to MCS, including project PTDC/MED-PAT/30385/2017, iNOVA4Health-UIDB/04462/2020, research infrastructure PPBI-POCI-01-0145-FEDER-022122, M-ERA.NET 2/0005/2016), Boehringer Ingelheim (to MCS), Fight for Sight UK (to MCS), Wellcome Trust grant number 212216/Z/18/Z/ (to CEF). MJH was funded by Moor-fields Eye Charity with the Bill Brown 1989 Charitable Trust PhD studentship 538158, MLS was funded by FCT-CEECIND/01536/2018, ACF was funded by FCT PhD studentship (PD/BD/135503/2018). This work was developed with the support from the research infrastructure PPBI-POCI-01-0145-FEDER-022122, co-financed by FCT (Portugal) and Lisboa2020, under the PORTUGAL2020 agreement (European Regional Development Fund) and this article is supported by the LYSOCIL project funded by the European Union?s Horizon 2020 programme under grant agreement No. 811087. Funding Information: Supported by Fundação para a Ciência e Tecnologia (FCT) – Portugal co-funded by FEDER under the PT2020 Partnership Agreement (to MCS, including project PTDC/MED-PAT/30385/2017, iNOVA4Health-UIDB/04462/2020, research infrastructure PPBI-POCI-01-0145-FEDER-022122, M-ERA.NET 2/0005/2016), Boehringer Ingelheim (to MCS), Fight for Sight UK (to MCS), Wellcome Trust grant number 212216/Z/18/Z/ (to CEF). MJH was funded by Moor-fields Eye Charity with the Bill Brown 1989 Charitable Trust PhD studentship 538158, MLS was funded by FCT-CEECIND/01536/2018, ACF was funded by FCT PhD studentship (PD/BD/135503/2018). This work was developed with the support from the research infrastructure PPBI-POCI-01-0145-FEDER-022122, co-financed by FCT (Portugal) and Lisboa2020, under the PORTUGAL2020 agreement (European Regional Development Fund) and this article is supported by the LYSOCIL project funded by the European Union’s Horizon 2020 programme under grant agreement No. 811087. Publisher Copyright: Copyright 2021 The Authors
dc.description.abstractPURPOSE. We aim to characterize the pathways required for autofluorescent granule (AFG) formation by RPE cells using cultured monolayers. METHODS. We fed RPE monolayers in culture with a single pulse of photoreceptor outer segments (POS). After 24 hours the cells started accumulating AFGs that were comparable to lipofuscin in vivo. Using this model, we used a variety of light and electron microscopical techniques, flow cytometry and Western blot to analyze the formation of AFGs. We also generated a mutant RPE line lacking cathepsin D by gene editing. RESULTS. AFGs seem to derive from incompletely digested POS-containing phagosomes and after 3 days are surrounded by a single membrane positive for lysosome markers. We show by various methods that lysosome-phagosome fusion is required for AFG formation, and that impairment of lysosomal pH or catalytic activity, particularly cathepsin D activity, enhances AF accumulation. CONCLUSIONS. We conclude that lysosomal dysfunction results in incomplete POS degradation and enhanced AFG accumulation.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent13461781
dc.identifier.doi10.1167/iovs.62.9.39
dc.identifier.issn0146-0404
dc.identifier.otherPURE: 33696510
dc.identifier.otherPURE UUID: 6ec3ec4e-d7cf-4de9-a649-49083e7a25a8
dc.identifier.otherScopus: 85111491693
dc.identifier.otherPubMed: 34313720
dc.identifier.otherWOS: 000685198300032
dc.identifier.urihttp://hdl.handle.net/10362/126474
dc.identifier.urlhttps://www.scopus.com/pages/publications/85111491693
dc.language.isoeng
dc.peerreviewedyes
dc.subjectAutofluorescent granules
dc.subjectLipofuscin
dc.subjectLysosome dysfunction
dc.subjectPhotoreceptor outer segments
dc.subjectRetinal pigmented epithelium
dc.subjectOphthalmology
dc.subjectSensory Systems
dc.subjectCellular and Molecular Neuroscience
dc.titleFormation of lipofuscin-like autofluorescent granules in the retinal pigment epithelium requires lysosome dysfunctionen
dc.typejournal article
degois.publication.issue9
degois.publication.titleInvestigative ophthalmology & visual science
degois.publication.volume62
dspace.entity.typePublication
person.familyNameSeabra
person.givenNameMiguel
person.identifier.ciencia-id2512-FAEF-E26F
person.identifier.orcid0000-0002-6404-4892
person.identifier.ridM-3280-2013
person.identifier.scopus-author-id7004369652
rcaap.rightsopenAccess
relation.isAuthorOfPublicationd6eeb095-df2d-4fd0-8241-ab826e5ecb1d
relation.isAuthorOfPublication.latestForDiscoveryd6eeb095-df2d-4fd0-8241-ab826e5ecb1d

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