ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an enzyme that catalyzes the biosynthesis of very long chain (VLC; e26 carbons) fatty acids. Mutations in ELOVL4 cause autosomal dominant Stargardt-like macular dystrophy (STGD3), a juvenile form of macular degeneration. Homozygous expression in humans causes ichthyosis, seizures, intellectual disability, and spastic quadriplegia, and death within the first few years of life. We determined that ELOVL4 synthesizes very long chain saturated (VLC-FA) and polyunsaturated (VLC-PUFA) fatty acids (eC26). ELOVL4 is expressed in retina, brain, skin, and testes, but the retina is the only tissue that has a reported dominant phenotype. In the current grant period, we found that 1) depletion of VLC-PUFA caused a slow death of rods and synaptic disorganization, 2) the mutant protein has no enzymatic activity, and 3) mislocalization of the mutant protein does not appear to contribute to the phenotype. In the studies proposed in this competing renewal, we will build upon our previous successes to determine the role of VLC-PUFA in the pathophysiology of retinal degeneration in STGD3.
Three specific aims are proposed: 1) To test the hypothesis that the retinal phenotype in the mouse can be rescued by VLC-PUFA, 2) To test the hypothesis that the retinal phenotype in the zebrafish can be rescued by VLC-PUFA, and 3) To determine the role of VLC-PUFA in the maintenance of healthy retinal pigment epithelium (RPE).
The protein that is mutated in dominant Stargardt-3 macular dystrophy synthesizes very long chain polyunsaturated fatty acids (VLC-PUFA) that are found in only a few human tissues, with the largest expression in the retina. Reduction in VLC-PUFA causes rod cell death. Dietary supplementation of these fatty acids may be an effective treatment of this juvenile form of macular degeneration.
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