Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration

  1. Federica Storti
  2. Katrin Klee
  3. Vyara Todorova
  4. Regula Steiner
  5. Alaa Othman
  6. Saskia van der Velde-Visser
  7. Marijana Samardzija
  8. Isabelle Meneau
  9. Maya Barben
  10. Duygu Karademir
  11. Valda Pauzuolyte
  12. Sanford L Boye
  13. Frank Blaser
  14. Christoph Ullmer
  15. Joshua L Dunaief
  16. Thorsten Hornemann
  17. Lucia Rohrer
  18. Anneke I den Hollander
  19. Arnold von Eckardstein
  20. Jürgen Fingerle
  21. Cyrille Maugeais
  22. Christian Grimm  Is a corresponding author
  1. University of Zurich, Switzerland
  2. Radboud University Medical Center, Netherlands
  3. University Hospital Zurich, Switzerland
  4. University of Florida, United States
  5. F Hoffmann-La Roche Ltd, Switzerland
  6. Scheie Eye Institute, University of Pennsylvania, United States
  7. 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

  1. Federica Storti

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  2. Katrin Klee

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  3. Vyara Todorova

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  4. Regula Steiner

    Institute of Clinical Chemistry, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  5. Alaa Othman

    Institute of Clinical Chemistry, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  6. Saskia van der Velde-Visser

    Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  7. Marijana Samardzija

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  8. Isabelle Meneau

    Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
  9. Maya Barben

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  10. Duygu Karademir

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  11. Valda Pauzuolyte

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  12. Sanford L Boye

    Ophthalmology and Molecular Genetics and Retina Gene Therapy Group, University of Florida, Gainesville, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8803-9369
  13. Frank Blaser

    Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
  14. Christoph Ullmer

    Roche Innovation Center Basel, F Hoffmann-La Roche Ltd, Basel, Switzerland
    Competing interests
    Christoph Ullmer, This author is an employee of F. Hoffmann-La Roche Ltd.
  15. Joshua L Dunaief

    Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  16. Thorsten Hornemann

    Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland
    Competing interests
    No competing interests declared.
  17. Lucia Rohrer

    Institute of Clinical Chemistry, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  18. Anneke I den Hollander

    Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  19. Arnold von Eckardstein

    Institute of Clinical Chemistry, University of Zurich, Schlieren, Switzerland
    Competing interests
    No competing interests declared.
  20. Jürgen Fingerle

    Natural and Medical Sciences Institute, University of Tübingen, Tübingen, Germany
    Competing interests
    Jürgen Fingerle, This author is a prevoius employee of F. Hoffmann-La Roche Ltd.
  21. Cyrille Maugeais

    Roche Innovation Center Basel, F Hoffmann-La Roche Ltd, Basel, Switzerland
    Competing interests
    Cyrille Maugeais, This author is a previous employee of F. Hoffmann-La Roche Ltd.
  22. Christian Grimm

    Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland
    For correspondence
    cgrimm@opht.uzh.ch
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9318-4352

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.

Reviewing Editor

  1. Jeremy Nathans, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: January 11, 2019
  2. Accepted: March 12, 2019
  3. Accepted Manuscript published: March 13, 2019 (version 1)
  4. Version of Record published: March 26, 2019 (version 2)

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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  1. Federica Storti
  2. Katrin Klee
  3. Vyara Todorova
  4. Regula Steiner
  5. Alaa Othman
  6. Saskia van der Velde-Visser
  7. Marijana Samardzija
  8. Isabelle Meneau
  9. Maya Barben
  10. Duygu Karademir
  11. Valda Pauzuolyte
  12. Sanford L Boye
  13. Frank Blaser
  14. Christoph Ullmer
  15. Joshua L Dunaief
  16. Thorsten Hornemann
  17. Lucia Rohrer
  18. Anneke I den Hollander
  19. Arnold von Eckardstein
  20. Jürgen Fingerle
  21. Cyrille Maugeais
  22. Christian Grimm
(2019)
Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration
eLife 8:e45100.
https://doi.org/10.7554/eLife.45100

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