Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3)
Abstract For many neurodegenerative disorders, expression of a pathological protein by one cell type impedes function of other cell types, which in turn contributes to the death of the first cell type. In transgenic mice modelling Stargardt-like (STGD3) maculopathy, human mutant ELOVL4 expression by...
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| Format: | Article |
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Nature Portfolio
2018-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-018-24357-4 |
| _version_ | 1818344732622848000 |
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| author | Camille Dejos Sharee Kuny Woo Hyun Han Heather Capel Hélène Lemieux Yves Sauvé |
| author_facet | Camille Dejos Sharee Kuny Woo Hyun Han Heather Capel Hélène Lemieux Yves Sauvé |
| author_sort | Camille Dejos |
| collection | DOAJ |
| description | Abstract For many neurodegenerative disorders, expression of a pathological protein by one cell type impedes function of other cell types, which in turn contributes to the death of the first cell type. In transgenic mice modelling Stargardt-like (STGD3) maculopathy, human mutant ELOVL4 expression by photoreceptors is associated with defects in the underlying retinal pigment epithelium (RPE). To examine how photoreceptors exert cytotoxic effects on RPE cells, transgenic ELOVL4 (TG1–2 line; TG) and wild-type (WT) littermates were studied one month prior (preclinical stage) to onset of photoreceptor loss (two months). TG photoreceptor outer segments presented to human RPE cells are recognized and internalized into phagosomes, but their digestion is delayed. Live RPE cell imaging pinpoints decreased numbers of acidified phagolysomes. In vivo, master regulator of lysosomal genes, transcription factor EB (TFEB), and key lysosomal enzyme Cathepsin D are both unaffected. Oxidative stress, as ruled out with high-resolution respirometry, does not play a role at such an early stage. Upregulation of CRYBA1/A3 and phagocytic cells (microglia/macrophages) interposed between RPE and photoreceptors support adaptive responses to processing delays. Impaired phagolysosomal maturation is observed in RPE of mice expressing human mutant ELOVL4 in their photoreceptors prior to photoreceptor death and associated vision loss. |
| first_indexed | 2024-12-13T16:51:09Z |
| format | Article |
| id | doaj.art-a678339708ca45858f64f495a3c5912a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T16:51:09Z |
| publishDate | 2018-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a678339708ca45858f64f495a3c5912a2022-12-21T23:38:02ZengNature PortfolioScientific Reports2045-23222018-04-018111410.1038/s41598-018-24357-4Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3)Camille Dejos0Sharee Kuny1Woo Hyun Han2Heather Capel3Hélène Lemieux4Yves Sauvé5Department of Ophthalmology and Visual Sciences, University of AlbertaDepartment of Ophthalmology and Visual Sciences, University of AlbertaDepartment of Ophthalmology and Visual Sciences, University of AlbertaDepartment of Physiology, University of AlbertaFaculty Saint-Jean, University of AlbertaDepartment of Ophthalmology and Visual Sciences, University of AlbertaAbstract For many neurodegenerative disorders, expression of a pathological protein by one cell type impedes function of other cell types, which in turn contributes to the death of the first cell type. In transgenic mice modelling Stargardt-like (STGD3) maculopathy, human mutant ELOVL4 expression by photoreceptors is associated with defects in the underlying retinal pigment epithelium (RPE). To examine how photoreceptors exert cytotoxic effects on RPE cells, transgenic ELOVL4 (TG1–2 line; TG) and wild-type (WT) littermates were studied one month prior (preclinical stage) to onset of photoreceptor loss (two months). TG photoreceptor outer segments presented to human RPE cells are recognized and internalized into phagosomes, but their digestion is delayed. Live RPE cell imaging pinpoints decreased numbers of acidified phagolysomes. In vivo, master regulator of lysosomal genes, transcription factor EB (TFEB), and key lysosomal enzyme Cathepsin D are both unaffected. Oxidative stress, as ruled out with high-resolution respirometry, does not play a role at such an early stage. Upregulation of CRYBA1/A3 and phagocytic cells (microglia/macrophages) interposed between RPE and photoreceptors support adaptive responses to processing delays. Impaired phagolysosomal maturation is observed in RPE of mice expressing human mutant ELOVL4 in their photoreceptors prior to photoreceptor death and associated vision loss.https://doi.org/10.1038/s41598-018-24357-4 |
| spellingShingle | Camille Dejos Sharee Kuny Woo Hyun Han Heather Capel Hélène Lemieux Yves Sauvé Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3) Scientific Reports |
| title | Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3) |
| title_full | Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3) |
| title_fullStr | Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3) |
| title_full_unstemmed | Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3) |
| title_short | Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3) |
| title_sort | photoreceptor induced rpe phagolysosomal maturation defects in stargardt like maculopathy stgd3 |
| url | https://doi.org/10.1038/s41598-018-24357-4 |
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