Lipofuscin Accumulation, Abnormal Electrophysiology, and Photoreceptor Degeneration in Mutant ELOVL4 Transgenic Mice: A Model for Macular Degeneration
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 t...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 11; pp. 4164 - 4169 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
National Academy of Sciences
15.03.2005
National Acad Sciences |
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Abstract | 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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AbstractList | 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. phagosome Stargardt disease photoreceptor retinal pigment epithelium 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. 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. 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. [PUBLICATION ABSTRACT] 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-hexatrie nyl]- 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. |
Author | Williams, D. S. Nathans, Jeremy Karan, G. Zhao, Y. Li, C. Yang, Z. Locke, K. G. Lillo, C. Birch, D. G. Zhang, K. Cameron, D. J. Vollmer-Snarr, H. R. Thirumalaichary, S. |
AuthorAffiliation | Department of Ophthalmology and Visual Science, † Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, and †† Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132; § Departments of Pharmacology and Neurosciences, University of California School of Medicine, San Diego, CA 92093-0912; ∥ Retina Foundation of the Southwest, Dallas, TX 75231; and ¶ Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602 |
AuthorAffiliation_xml | – name: Department of Ophthalmology and Visual Science, † Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, and †† Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132; § Departments of Pharmacology and Neurosciences, University of California School of Medicine, San Diego, CA 92093-0912; ∥ Retina Foundation of the Southwest, Dallas, TX 75231; and ¶ Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602 |
Author_xml | – sequence: 1 givenname: G. surname: Karan fullname: Karan, G. – sequence: 2 givenname: C. surname: Lillo fullname: Lillo, C. – sequence: 3 givenname: Z. surname: Yang fullname: Yang, Z. – sequence: 4 givenname: D. J. surname: Cameron fullname: Cameron, D. J. – sequence: 5 givenname: K. G. surname: Locke fullname: Locke, K. G. – sequence: 6 givenname: Y. surname: Zhao fullname: Zhao, Y. – sequence: 7 givenname: S. surname: Thirumalaichary fullname: Thirumalaichary, S. – sequence: 8 givenname: C. surname: Li fullname: Li, C. – sequence: 9 givenname: D. G. surname: Birch fullname: Birch, D. G. – sequence: 10 givenname: H. R. surname: Vollmer-Snarr fullname: Vollmer-Snarr, H. R. – sequence: 11 givenname: D. S. surname: Williams fullname: Williams, D. S. – sequence: 12 givenname: K. surname: Zhang fullname: Zhang, K. – sequence: 13 givenname: Jeremy surname: Nathans fullname: Nathans, Jeremy |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/15749821$$D View this record in MEDLINE/PubMed |
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Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 To whom correspondence may be addressed. E-mail: kang.zhang@hmbg.utah.edu, dswilliams@ucsd.edu, or hrvs@chem.byu.edu. This paper was submitted directly (Track II) to the PNAS office. Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 27, 2005 Author contributions: D.S.W., D.G.B., H.V.R.S., and K.Z. designed research; G.K., C. Lillo, Z.Y., D.J.C., K.G.L., Y.Z., C. Li, and K.Z. performed research; G.K., C. Lillo, Z.Y., D.J.C., K.G.L., Y.Z., D.S.W., and K.Z. analyzed data; G.K., D.G.B., D.S.W., H.V.R.S., and K.Z. wrote the paper; and G.K., D.G.B., D.S.W., D.J.C., and K.Z. edited photomicrographs. G.K., C.L., Z.Y., and D.J.C. contributed equally to this work. Abbreviations: AMD, age-related macular degeneration; STGD, Stargardt macular dystrophy; RPE, retinal pigment epithelium; IRBP, interphotoreceptor retinoid-binding protein; ERG, electroretinography; A2E, 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. |
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Snippet | Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in... |
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SubjectTerms | Animals Biological Sciences Complementary DNA Disease Models, Animal Electrophysiology Eye Proteins - genetics Eye Proteins - metabolism Fatty acids Gene expression Humans Isomers Lipofuscin - metabolism Macular degeneration Macular Degeneration - genetics Macular Degeneration - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Transgenic Microscopy, Electron Mutation Neurology Photoreceptor Cells - metabolism Photoreceptor Cells - ultrastructure Photoreceptors Polymerase chain reaction Retina Retina - metabolism Retina - pathology Reverse transcriptase polymerase chain reaction Transgenes Transgenic animals |
Title | Lipofuscin Accumulation, Abnormal Electrophysiology, and Photoreceptor Degeneration in Mutant ELOVL4 Transgenic Mice: A Model for Macular Degeneration |
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