Recent studies have identified 3 separate mutations in a gene in dominant Stargardt-3 macular dystrophy (STGD3, a juvenile form of macular degeneration) that encodes a protein with significant sequence homology to a family of proteins first identified in yeast that function in the elongation of fatty acids. The STGD3 gene was named ELOVL4, for Elongation of very long chain fatty acids-4. In the current grant period, we identified the enzymatic step catalyzed by the ELOVL4 protein to be the elongation of C26 saturated and polyunsaturated fatty acids (PUFA) to their C28 products. Identification of the enzymatic step catalyzed by ELOVL4 allows us to pursue focused studies to determine the role of VLC-PUFA in the retinal phenotype in animal models of STGD3 disease, several of which we have found to have reduced retinal levels of these fatty acids.
Five specific aims are proposed for this 5-year competing renewal: 1. To test the hypothesis that loss of retinal VLC-PUFA is responsible for the retinal phenotype found in animal models of STGD3. This is a key study because it will allow us to differentiate between the effects of VLC-PUFA deficiency and protein mis-location on the development of the retinal phenotype. 2. To test the hypothesis that the retinal phenotype can be rescued by VLC-PUFA. If the retinal phenotype is due to loss of retinal VLC-PUFA, we will express ELOVL4 in liver and retinal pigment epithelium to provide an endogenous source of VLC-PUFA. Dietary supplementation of these fatty acids is not currently possible because there is no commercial source. 3. To test the hypothesis that mis-direction of ELOVL4 in photoreceptors contributes to the retinal phenotype. It is possible that the retinal phenotype is due to a combination of VLC-PUFA deficiency and mis-direction of ELOVL4. We will test this hypothesis in animal and in vitro models. 4. To determine the biochemical properties of the ELOVL4 enzyme. We will determine the enzymatic activities of WT and mutant enzyme ELOVL4, as well as their substrate specificities and subcellular localization. 5. To search for the physiological function VLC-PUFA. We will test the neuroprotective properties of VLC-PUFA and determine if they affect gene expression.

Public Health Relevance

We discovered that the abnormal protein in Stargardt-3 macular dystrophy is involved in the biosynthesis of very long chain polyunsaturated fatty acids (VLC-PUFA) that are found in only a few human tissues;the largest expression is in the retina. Dietary supplementation of these fatty acids may be an effective treatment of this juvenile form of macular degeneration.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
United States
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Mandal, Nawajes A; Tran, Julie-Thu A; Zheng, Lixin et al. (2014) In vivo effect of mutant ELOVL4 on the expression and function of wild-type ELOVL4. Invest Ophthalmol Vis Sci 55:2705-13
Marchette, L D; Sherry, D M; Brush, R S et al. (2014) Very long chain polyunsaturated fatty acids and rod cell structure and function. Adv Exp Med Biol 801:637-45
Bennett, Lea D; Hopiavuori, Blake R; Brush, Richard S et al. (2014) Examination of VLC-PUFA-deficient photoreceptor terminals. Invest Ophthalmol Vis Sci 55:4063-72
Agbaga, Martin-Paul; Logan, Sreemathi; Brush, Richard S et al. (2014) Biosynthesis of very long-chain polyunsaturated fatty acids in hepatocytes expressing ELOVL4. Adv Exp Med Biol 801:631-6
Bennett, Lea D; Brush, Richard S; Chan, Michael et al. (2014) Effect of reduced retinal VLC-PUFA on rod and cone photoreceptors. Invest Ophthalmol Vis Sci 55:3150-7
Logan, Sreemathi; Agbaga, Martin-Paul; Chan, Michael D et al. (2014) Endoplasmic reticulum microenvironment and conserved histidines govern ELOVL4 fatty acid elongase activity. J Lipid Res 55:698-708
Logan, Sreemathi; Anderson, Robert E (2014) Dominant Stargardt Macular Dystrophy (STGD3) and ELOVL4. Adv Exp Med Biol 801:447-53
Agbaga, Martin-Paul; Tam, Beatrice M; Wong, Jenny S et al. (2014) Mutant ELOVL4 that causes autosomal dominant stargardt-3 macular dystrophy is misrouted to rod outer segment disks. Invest Ophthalmol Vis Sci 55:3669-80
Garanto, Alejandro; Mandal, Nawajes A; Egido-Gabas, Meritxell et al. (2013) Specific sphingolipid content decrease in Cerkl knockdown mouse retinas. Exp Eye Res 110:96-106
Logan, Sreemathi; Agbaga, Martin-Paul; Chan, Michael D et al. (2013) Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy. Proc Natl Acad Sci U S A 110:5446-51

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