Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration
- University of Zurich, Switzerland
- Radboud University Medical Center, Netherlands
- University Hospital Zurich, Switzerland
- University of Florida, United States
- F Hoffmann-La Roche Ltd, Switzerland
- Scheie Eye Institute, University of Pennsylvania, United States
- University of Tübingen, Germany
Abstract
Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 (ABCA1), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the ABCA1 AMD risk-conferring allele decreases ABCA1 expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Vontobel Stiftung
- Federica Storti
Roche (RPF 378)
- Federica Storti
- Christian Grimm
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_173008)
- Vyara Todorova
- Marijana Samardzija
- Maya Barben
- Christian Grimm
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the regulations of the Veterinary Authorities of Kanton Zurich, Switzerland (study approval reference numbers: ZH141/2016 and ZH216/2015).
Human subjects: The study was approved by the local ethical committee at the Radboud University Medical Center, The Netherlands, and was performed in accordance with the tenets of the Declaration of Helsinki. Individuals were selected from the European Genetic Database (EUGENDA, https://www.eugenda.org/), a large multicenter database for clinical and molecular analysis of AMD, and provided written informed consent before participation.
Copyright
© 2019, Storti et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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