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.
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.
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