September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Elucidating the role of Retinal Pigment Epithelium (RPE)-specific ABCA4 in Stargardt disease
Author Affiliations & Notes
  • Tamara Lee Lenis
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Zhichun Jiang
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Shanta Sarfare
    Ora, Inc., Andover, Massachusetts, United States
  • Andrew Le
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Shannan Eddington
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Dean Bok
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Robert S Molday
    University of British Columbia, Vancouver, British Columbia, Canada
  • Steven Nusinowitz
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Michael Redmond
    National Eye Institute, Bethesda, Maryland, United States
  • Gabriel H Travis
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Roxana A Radu
    Stein Eye Institute, UCLA, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Tamara Lenis, None; Zhichun Jiang, None; Shanta Sarfare, None; Andrew Le, None; Shannan Eddington, None; Dean Bok, None; Robert Molday, None; Steven Nusinowitz, None; Michael Redmond, None; Gabriel Travis, None; Roxana Radu, None
  • Footnotes
    Support  NIH-R01 EY025002, JSEI NIH Core Grant EY00031-48, Macula Vision Research Foundation Sponsor Award 20142217, Gerald Oppenheimer Family Foundation
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3177. doi:
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      Tamara Lee Lenis, Zhichun Jiang, Shanta Sarfare, Andrew Le, Shannan Eddington, Dean Bok, Robert S Molday, Steven Nusinowitz, Michael Redmond, Gabriel H Travis, Roxana A Radu; Elucidating the role of Retinal Pigment Epithelium (RPE)-specific ABCA4 in Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3177.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Recessive Stargardt disease (STGD1) is an inherited macular degeneration caused by mutations in ABCA4. Mice with a null mutation in the Abca4 gene are characterized by the deposition of bis-retinoids and lipofuscin pigments in the RPE, dysregulation of the complement system, and late-onset photoreceptor degeneration. ABCA4 is thought to be expressed exclusively in photoreceptor outer-segment (OS) discs, and to function as an inward-directed flippase for N-ret-PE, the conjugate of retinaldehyde and phosphatidylethanolamine. However, in dark-reared Abca4-/- mice with less OS retinaldehyde burden, RPE bis-retinoid accumulation is still seen, suggesting that RPE-specific ABCA4 plays a protective role. Here, we show that ABCA4 is also expressed in RPE endo-lysosomal membranes, where it performs a similar function as in OS discs.

Methods : We generated transgenic mice using a construct that contains the normal mouse Abca4 coding-region downstream of the RPE-specific promoter. We crossed this transgene onto the Abca4 null background to obtain a line that expresses ABCA4 in the RPE, but not in the retina (Abca4-Tg5 mice). ABCA4 expression was determined by qRT-PCR, immunoblotting, and immunohistochemistry. Retinoids were measured by HPLC. Photoreceptor degeneration was evaluated by spectral-domain optical coherence tomography and light microscopy of retina sections.

Results : We demonstrated ABCA4 expression in normal RPE cells from several sources by qRT-PCR and immunoblotting. To confirm these observations, we showed that Mertk-/- mice, which do not phagocytose photoreceptor OS, also contained the Abca4 mRNA and protein. Levels of bis-retinoids and fluorescent lipofuscin pigments in Abca4-Tg5 RPE were about two-fold lower when compared to non-transgenic Abca4-/- RPE. Further, Abca4-Tg5 mice exhibited photoreceptor preservation at one year, in contrast to age-matched non-transgenic Abca4-/- mice, which lost approximately 40% of photoreceptors.

Conclusions : ABCA4 is expressed in intracellular membranes of RPE cells, in addition to photoreceptor OS discs. The Abca4-Tg5 mouse shows reduced bisretinoid accumulation and photoreceptor preservation, suggesting an active role of ABCA4 in the RPE. This study explains the accumulation of bis-retinoids seen in dark reared Abca4-/- mice by demonstrating that RPE-specific ABCA4 plays a key role in recycling retinoids released from phagocytosed OS.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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