Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration
Open accessAbstract
Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness.
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Defective OS phagosome motility and degradation has been found in a mouse model of Stargardt macular degeneration (type 3), leading to phagosome accumulation, RPE pathogenesis, and photoreceptor cell death.
“In a second example, defective OS phagosome motility and degradation has been found in a mouse model of Stargardt macular degeneration (type 3) (Esteve-Rudd et al., 2018), leading to phagosome accumulation, RPE pathogenesis, and photoreceptor cell death (Karan et al., 2005).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Karan et al., 2005
Cites
Prevalence of Age-Related Macular Degeneration in the United States
The Eye Diseases Prevalence Research Group* (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.564 · Cited by 2,742 · see citing works
Chemistry and metabolism of lipids in the vertebrate retina
Fliesler, A. J., & Anderson, R. E. (1983) · Progress in Lipid Research · doi:10.1016/0163-7827(83)90004-8 · Cited by 1,052 · see citing works
Weng, J., Mata, N. L., Azarian, S. M., Tzekov, R. T., Birch, D. G., & Travis, G. H. (1999) · Cell · doi:10.1016/s0092-8674(00)80602-9 · Cited by 881 · see citing works
Self-citationAge-related macular degeneration
Bressler, N. M., Bressler, S. B., & Fine, S. L. (1988) · Survey of Ophthalmology · doi:10.1016/0039-6257(88)90052-5 · Cited by 710 · see citing works
Parish, C. A., Hashimoto, M., Nakanishi, K., Dillon, J., & Sparrow, J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14609 · Cited by 474 · see citing works
Retinal age pigments generated by self-assembling lysosomotropic detergents
Eldred, G. E., & Lasky, M. R. (1993) · Nature · doi:10.1038/361724a0 · Cited by 461 · see citing works
Zhang, K., Kniazeva, M., Han, M., Li, W., Yu, Z., Yang, Z., Li, Y., Metzker, M. L., Allikmets, R. L., Zack, D. J., et al. (2001) · Nature Genetics · doi:10.1038/83817 · Cited by 453 · see citing works
Self-citationFluorophores of the human retinal pigment epithelium: Separation and spectral characterization
Eldred, G. E., & Katz, M. L. (1988) · Experimental Eye Research · doi:10.1016/0014-4835(88)90025-5 · Cited by 301 · see citing works
The fatty acid chain elongation system of mammalian endoplasmic reticulum
Cinti, D. L., Cook, L. S., Nagi, M. N., & Suneja, S. K. (1992) · Progress in Lipid Research · doi:10.1016/0163-7827(92)90014-a · Cited by 241 · see citing works
Radu, R. A., Mata, N. L., Nusinowitz, S., Liu, X., Sieving, P. A., & Travis, G. H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0737855100 · Cited by 227 · see citing works
Tvrdík, P., Westerberg, R., Silve, S., Asadi, A., Jakobsson, A., Cannon, B., Loison, G., & Jacobsson, A. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.3.707 · Cited by 218 · see citing works
Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene.
Bernstein, P. S., Tammur, J., Singh, N., Hutchinson, A. A., Dixon, M., Pappas, C. M., Zabriskie, N. A., Zhang, K., Petrukhin, K. E., Leppert, M., et al. (2001) · PubMed · Cited by 156 · see citing works
Self-citationHood, D. C., & Birch, D. G. (1993) · Vision Research · doi:10.1016/0042-6989(93)90027-t · Cited by 148 · see citing works
Self-citationFeeney-Burns, L., & Ge, E. (1983) · PubMed · Cited by 143 · see citing works
Birch, D. G., Hood, D. C., Nusinowitz, S., & Pepperberg, D. R. (1995) · PubMed · Cited by 113 · see citing works
Self-citationEdwards, A. O., Donoso, L. A., & Ritter, R. (2001) · PubMed · Cited by 100 · see citing works
Mandal, M. N. A., Ambasudhan, R., WONG, P. W. K., Gage, P. J., Sieving, P. A., & Ayyagari, R. (2003) · Genomics · doi:10.1016/j.ygeno.2003.09.020 · Cited by 93 · see citing works
A Novel Mutation in the ELOVL4 Gene Causes Autosomal Dominant Stargardt-like Macular Dystrophy
Maugeri, A., Meire, F. M., Hoyng, C. B., Vink, C., Regemorter, N. V., Karan, G., Yang, Z., Cremers, F. P. M., & Zhang, K. (2004) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.04-0078 · Cited by 90 · see citing works
Self-citationDocosahexaenoic acid in red blood cells of patients with X-linked retinitis pigmentosa.
Hoffman, D. R., & Birch, D. G. (1995) · PubMed · Cited by 70 · see citing works
Self-citationAnderson, R. E., Maude, M. B., McClellan, M. E., Matthes, M. T., Yasumura, D., & LaVail, M. M. (2002) · PubMed · Cited by 67 · see citing works
Liou, G. I., Li, G., Al‐Ubaidi, M. R., Matragoon, S., Hanten, G. R., Baehr, W., & Overbeek, P. A. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38895-7 · Cited by 58 · see citing works
Ambasudhan, R., Wang, X., Jablonski, M. M., Thompson, D. A., Lagali, P. S., WONG, P. W. K., Sieving, P. A., & Ayyagari, R. (2003) · Genomics · doi:10.1016/j.ygeno.2003.10.004 · Cited by 54 · see citing works
Plasma lipid abnormalities in retinitis pigmentosa and related conditions.
Converse, C. A., Hammer, H. M., Packard, C. J., & Shepherd, J. (1983) · PubMed · Cited by 53 · see citing works
Zhang, X.-M., Yang, Z., Karan, G., Hashimoto, T., Baehr, W., Yang, X.-J., & Zhang, K. (2003) · PubMed · Cited by 41 · see citing works
Self-citationAn international standard for electroretinography
Marmor, M. F. (1989) · Documenta Ophthalmologica · doi:10.1007/bf00154485 · Cited by 36 · see citing works
Hubbard, A. F. (2006) · Archives of Ophthalmology · doi:10.1001/archopht.124.2.257 · Cited by 35 · see citing works
MacDonald, I. M. (2004) · British Journal of Ophthalmology · doi:10.1136/bjo.2003.024299 · Cited by 34 · see citing works
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Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents
Travis, G. H., Golczak, M., Moise, A. R., & Palczewski, K. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105225 · Cited by 419 · see citing works
The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422 · see citing works
Self-citationAnimal models of age related macular degeneration
Pennesi, M. E., Neuringer, M., & Courtney, R. J. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.06.003 · Cited by 391 · see citing works
The 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
A comparison of some organizational characteristics of the mouse central retina and the human macula
Volland, S., Esteve-Rudd, J., Hoo, J., Yee, C., & Williams, D. S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125631 · Cited by 229 · see citing works
Self-citationTuo, J., Bojanowski, C. M., Zhou, M., Shen, D., Ross, R. J., Rosenberg, K. I., Cameron, D. J., Yin, C., Kowalak, J. A., Zhuang, Z., et al. (2007) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-0051 · Cited by 205 · see citing works
Self-citationPhospholipid meets all-trans-retinal: the making of RPE bisretinoids
Sparrow, J. R., Wu, Y., Kim, C. Y., & Zhou, J. (2010) · Journal of Lipid Research · doi:10.1194/jlr.r000687 · Cited by 193 · see citing works
Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein
Agbaga, M.-P., Mandal, M. N. A., & Anderson, R. E. (2010) · Journal of Lipid Research · doi:10.1194/jlr.r005025 · Cited by 167 · see citing works
Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)
Ramkumar, H. L., Zhang, J., & Chan, C.-C. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.02.002 · Cited by 163 · see citing works
Retinoids for treatment of retinal diseases
Palczewski, K. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.03.001 · Cited by 111 · see citing works
Mouse models of age-related macular degeneration
Elizabeth Rakoczy, P., Yu, M. J. T., Nusinowitz, S., Chang, B., & Heckenlively, J. R. (2006) · Experimental Eye Research · doi:10.1016/j.exer.2005.10.012 · Cited by 107 · see citing works
Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium
Bhosale, P., Serban, B., & Bernstein, P. S. (2009) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.09.012 · Cited by 85 · see citing works
Ma, L., Kaufman, Y., Zhang, J., & Washington, I. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178657 · Cited by 83 · see citing works
Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration
Molday, R. S., & Zhang, K. (2010) · Progress in Lipid Research · doi:10.1016/j.plipres.2010.07.002 · Cited by 82 · see citing works
Self-citationA high omega-3 fatty acid diet reduces retinal lesions in a murine model of macular degeneration
Tuo, J., Ross, R. J., Herzlich, A. A., Shen, D., Ding, X., Zhou, M., Coon, S. L., Hussein, N., Salem, N., & Chan, C.-C. (2009) · The American Journal of Pathology · doi:10.2353/ajpath.2009.090089 · Cited by 80 · see citing works
Kaufman, Y., Ma, L., & Washington, I. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178640 · Cited by 78 · see citing works
Lyzogubov, V. V., Bora, P. S., Wu, X., Horn, L. E., de Roque, R., Rudolf, X. V., Atkinson, J. P., & Bora, N. S. (2016) · The American Journal of Pathology · doi:10.1016/j.ajpath.2016.03.021 · Cited by 45 · see citing works
Anderson, D. M. G., Ablonczy, Z., Koutalos, Y., Hanneken, A. M., Spraggins, J. M., Calcutt, M. W., Crouch, R. K., Caprioli, R. M., & Schey, K. L. (2017) · Scientific Reports · doi:10.1038/s41598-017-17402-1 · Cited by 48 · see citing works
Esteve-Rudd, J., Hazim, R. A., Diemer, T., Paniagua, A. E., Volland, S., Umapathy, A., & Williams, D. S. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1709211115 · Cited by 42 · see citing works
Self-citationAgbaga, M.-P., Tam, B. M., Wong, J. S., Yang, L. L., Anderson, R. E., & Moritz, O. L. (2014) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.13-13099 · Cited by 26 · see citing works
- Authors
- Karan, G., Lillo, C., Yang, Z., Cameron, D. J., Locke, K. G., Zhao, Y., Thirumalaichary, S., Li, C., Birch, D. G., Vollmer-Snarr, H. R., Williams, D. S., & Zhang, K.
- Affiliations
- Brigham Young University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-03-04
- Volume
- 102
- Issue
- 11
- Pages
- 4164-4169
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC554798
- OpenAlex
- W2043251036
- Cited by
- 182
- References
- 27
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 10 · 2020: 6 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 4 · 2015: 9 · 2014: 12 · 2013: 9 · 2012: 13
- 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
- American Health Assistance Foundation
- Ronald McDonald House Charities
- Karl Kirchgessner Foundation
- Research to Prevent Blindness
- Brigham Young University
- Deutsches Krebsforschungszentrum
- National Institutes of Health (5p30ey012598-05, M01-RR00064)
- National Eye Institute (R01EY014448, R01EY05235, R01EY13408, P30-EY012598, R01EY013408, P30-EY12598, R01EY014428, R01EY14428, R01EY14448, R01EY007042, R01EY005235)
- National Center for Research Resources (M01-RR 00064, M01RR000064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- ELOVL4, macular degeneration, lipofuscin accumulation, retinal pigment epithelium atrophy, photoreceptor degeneration, transgenic mouse model, retinal electrophysiology, age-related macular degeneration
- MeSH terms
- Animals, Disease Models, Animal, Electrophysiology, Eye Proteins, Humans, Lipofuscin, Macular Degeneration, Membrane Proteins, Mice, Transgenic, Microscopy, Electron, Photoreceptor Cells, Retina, Mice
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