ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal
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Significance: ABCA4 is an ATP-binding cassette transporter encoded by the gene responsible for Stargardt macular degeneration, an inherited retinopathy associated with severe vision loss. Previous studies have shown that ABCA4 facilitates the clearance of all- trans -retinal from photoreceptor disc membranes following photoexcitation. More recent studies implicate excess 11- cis -retinal in the etiology of Stargardt disease. In this study we show the ABCA4 can transport the N -11- cis -retinylidene-phosphatidylethanolamine (PE), the Schiff-base adduct of 11- cis -retinal and PE, across membranes. This transport activity together with chemical isomerization of N -11- cis -retinylidene-PE to its all- trans isomer and reduction to all- trans -retinol can prevent the accumulation of excess 11- cis -retinal and potentially toxic bisretinoid compounds implicated in Stargardt and related retinal degenerative diseases.
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ABCA4 dysfunction leads to the accumulation of vitamin A derivatives and toxic compounds in photoreceptor outer segments because they cannot be efficiently removed.
“ABCA4 dysfunction leads to the accumulation of vitamin A derivatives and toxic compounds, as they cannot be efficiently removed from the photoreceptor outer segment.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [93]
Trapped vitamin A derivatives and toxic compounds can react nonenzymatically to form toxic bisretinoids.
“Trapped vitamin A derivatives and toxic compounds can react nonenzymatically, leading to the formation of toxic bisretinoids.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [93]
A2E is insoluble, tends to aggregate, and accumulates as lipofuscin deposits in RPE cells, compromising RPE function and leading to cell death.
“The latter are insoluble, have a tendency to aggregate and accumulate as lipofuscin deposits in the RPE cells, compromising RPE function and leading to cell death.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [93]
Upon phagocytosis of outer segments by RPE cells, bisretinal compounds can be hydrolyzed by lysosomal enzymes to the highly toxic metabolite A2E.
“Upon phagocytosis of outer segments by adjacent RPE cells, the bisretinal compounds can be hydrolyzed by lysosomal enzymes to highly toxic metabolite A2E.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [93]
Cites
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“In the absence of ABCA4, 11-cis-retinal and its Schiff-base conjugate will accumulate in disk membranes leading to the formation of A2E and other bisretinoids in photoreceptors and lipofuscin deposits in RPE cells following phagocytosis of outer segments.”
BackgroundInfluentialThe bisretinoids of retinal pigment epithelium
Sparrow, J. R., Gregory-Roberts, E., Yamamoto, K., Blonska, A., Ghosh, S. K., Ueda, K., & Zhou, J. (2012) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2011.12.001 · Cited by 392 · see citing works
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Self-citationABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer
Quazi, F., Lenevich, S., & Molday, R. S. (2012) · Nature Communications · doi:10.1038/ncomms1927 · Cited by 276 · see citing works
Self-citationMolday, R. S., Zhong, M., & Quazi, F. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.02.004 · Cited by 182 · see citing works
Self-citationBeharry, S., Zhong, M., & Molday, R. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405216200 · Cited by 174 · see citing works
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Lenis, T. L., Hu, J., Ng, S. Y., Jiang, Z., Sarfare, S., Lloyd, M. B., Esposito, N. J., Samuel, W., Jaworski, C., Bok, D., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802519115 · Cited by 158 · see citing works
The Role of Vitamin A in Retinal Diseases
Sajovic, J., Meglič, A., Glavač, D., Markelj, Š., Hawlina, M., & Fakin, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031014 · Cited by 109 · see citing works
“Consequently, dysfunction and loss of photoreceptors they support occurs [69,71,93].”
BackgroundRetinoids and Retinal Diseases
Kiser, P. D., & Palczewski, K. (2016) · Annual Review of Vision Science · doi:10.1146/annurev-vision-111815-114407 · Cited by 108 · see citing works
Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration
Molday, R. S., Garces, F. A., Scortecci, J. F., & Molday, L. L. (2022) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.101036 · Cited by 107 · see citing works
Self-citationStargardt macular dystrophy and evolving therapies
Hussain, R. M., Ciulla, T. A., Berrocal, A. M., Gregori, N. Z., Flynn, H. W., & Lam, B. L. (2018) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2018.1513486 · Cited by 56 · see citing works
An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
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Ekesten, B., Mäkeläinen, S., Ellis, S., Kjellström, U., & Bergström, T. F. (2022) · Translational Vision Science & Technology · doi:10.1167/tvst.11.2.36 · Cited by 3 · see citing works
- Authors
- Quazi, F., & Molday, R. S.
- Affiliations
- University of British Columbia (CA)
- ORCID
- Molday, Robert S.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-03-20
- Volume
- 111
- Issue
- 13
- Pages
- 5024-5029
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3977269
- OpenAlex
- W2035143113
- Cited by
- 129
- References
- 10
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 10 · 2021: 17 · 2020: 14 · 2019: 9 · 2018: 7 · 2017: 9 · 2016: 8 · 2015: 14 · 2014: 4
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (EY02422, R01EY002422)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- ABCA4, ABC transporters, 11-cis-retinal, visual cycle, retinol dehydrogenase, all-trans-retinol
- MeSH terms
- Adenosine Triphosphate, Animals, Biological Transport, Cattle, Isomerism, Models, Biological, Phosphatidylcholines, Phosphatidylethanolamines, Proteolipids, Retinoids, Rod Cell Outer Segment, Vitamin A, ATP-Binding Cassette Transporters, Cytoprotection, Photoreceptor Cells, Vertebrate, Sus scrofa, Mice
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