Toms, M;
Burgoyne, T;
Tracey-White, D;
Richardson, R;
Dubis, AM;
Webster, AR;
Futter, C;
(2019)
Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy.
Scientific Reports
, 9
, Article 3793. 10.1038/s41598-019-40507-8.
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Abstract
Mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We examined the retina of kcnj13 mutant zebrafish (obelixtd15, c.502T > C p.[Phe168Leu]) to provide new insights into the pathophysiology underlying these conditions. Detailed phenotyping of obelixtd15 fish revealed a late onset retinal degeneration at 12 months. Electron microscopy of the obelixtd15 retinal pigment epithelium (RPE) uncovered reduced phagosome clearance and increased mitochondrial number and size prior any signs of retinal degeneration. Melanosome distribution was also affected in dark-adapted 12-month obelixtd15 fish. At 6 and 12 months, ATP levels were found to be reduced along with increased expression of glial fibrillary acidic protein and heat shock protein 60. Quantitative RT-PCR of polg2, fis1, opa1, sod1/2 and bcl2a from isolated retina showed expression changes consistent with altered mitochondrial activity and retinal stress. We propose that the retinal disease in this model is primarily a failure of phagosome physiology with a secondary mitochondrial dysfunction. Our findings suggest that alterations in the RPE and photoreceptor cellular organelles may contribute to KCNJ13-related retinal degeneration and provide a therapeutic target.
| Type: | Article |
|---|---|
| Title: | Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41598-019-40507-8 |
| Publisher version: | http://doi.org/10.1038/s41598-019-40507-8 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10070073 |
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