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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Agbaga, Martin-Paul; Merriman, Dana K; Brush, Richard S et al. (2018) Differential composition of DHA and very-long-chain PUFAs in rod and cone photoreceptors. J Lipid Res 59:1586-1596
Hopiavuori, Blake R; Deák, Ferenc; Wilkerson, Joseph L et al. (2018) Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency. Mol Neurobiol 55:1795-1813
Hopiavuori, Blake R; Agbaga, Martin-Paul; Brush, Richard S et al. (2017) Regional changes in CNS and retinal glycerophospholipid profiles with age: a molecular blueprint. J Lipid Res 58:668-680
Azadi, Seifollah; Brush, Richard S; Anderson, Robert E et al. (2016) Class I Phosphoinositide 3-Kinase Exerts a Differential Role on Cell Survival and Cell Trafficking in Retina. Adv Exp Med Biol 854:363-9
Simón, María Victoria; Agnolazza, Daniela L; German, Olga Lorena et al. (2016) Synthesis of docosahexaenoic acid from eicosapentaenoic acid in retina neurons protects photoreceptors from oxidative stress. J Neurochem 136:931-46
Bennett, Lea D; Anderson, Robert E (2016) Current Progress in Deciphering Importance of VLC-PUFA in the Retina. Adv Exp Med Biol 854:145-51
Agbaga, Martin-Paul (2016) Different Mutations in ELOVL4 Affect Very Long Chain Fatty Acid Biosynthesis to Cause Variable Neurological Disorders in Humans. Adv Exp Med Biol 854:129-35
Rajala, Raju V S; Kanan, Yogita; Anderson, Robert E (2016) Photoreceptor Neuroprotection: Regulation of Akt Activation Through Serine/Threonine Phosphatases, PHLPP and PHLPPL. Adv Exp Med Biol 854:419-24
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
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

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