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W. Kedzierski, S. N. Jackson, A. S. Woods; A Mouse Model of Stargardt Disease-3: Molecular Pathogenesis and Potential Treatments. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4031. doi: https://doi.org/.
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Stargardt disease-3 (STGD3) is caused by mutations in elongase of very long chain fatty acids-4 (ELOVL4). Recently, we generated a mouse model of STGD3, the Stgd3 gene-knockin mice that carry a human pathogenic 5-bp deletion in the mouse Elovl4 gene. The mice demonstrate reduced ERG and increased lipofuscin accumulation, two early features of the human pathology. Additionally, these mice show retinal deficiency of the phosphatidylcholine (PC) species that contains acyl residues of polyunsaturated extremely long chain C32-C36 fatty acids (ELCFAs). Our continuing studies of Stgd3 mice are focused on the molecular pathogenesis and potential treatments of the disease.
Three groups of Stgd3-heterozygous mice are fed a standard rodent diet. In addition, two of them receive a dietary supplement of: either (a) polyunsaturated ELCFAs or (b) fish oil rich in ELCFA precursors and DHA. After treatment, the mice are euthanized and their retinas collected. Isolated retinal lipids are then analyzed using mass spectrometry. Three groups of wild-type mice will serve as control animals and will be subjected to identical treatments.
In the mouse retina, ELCFAs are synthesized by Elovl4. The ELCFA chain length is determined by the Elovl4 activity. In Stgd3-heterozygous mice, the human STGD3-pathogenic mutation selectively reduces amounts of retinal C32-C36 acyl PCs. The levels of PCs with the longer C34 and C36 acyl chains are reduced more than the level of C32 acyl PC. The ongoing experiments are testing whether dietary supplementation of polyunsaturated ELCFAs or their precursors can correct deficiency of retinal C32-C36 acyl PCs in Stgd3 mice.
We demonstrated that polyunsaturated ELCFAs play an important role in retinal physiology. Their role is independent of DHA's role. The STGD3 mutation reduces synthesis of ELCFAs causing deficiency of retinal C32-C36 acyl PCs. It results in altered photoreceptor membrane lipid composition, followed by reduced ERG and increased lipofuscin accumulation. We expect that the retinal deficiency of C32-C36 acyl PCs can be corrected by dietary supplementation of polyunsaturated ELCFAs. This treatment may prevent the pathological retinal changes observed in both STGD3 patients and Stgd3 mice.
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