P23H and S334ter opsin mutations: Increasing photoreceptor outersegment n-3 fatty acid content does not affect the course of retinaldegeneration

[摘要] Purpose: The n-3 polyunsaturated fatty acids (PUFA) facilitateretinal development and function. Rats carrying transgenes with P23H andS334ter rhodopsin mutations lose their photoreceptors and have lowerlevels of 22:6n-3 in rod photoreceptor outer segments (ROS) than wildtype (WT) animals. We tested the hypothesis that the rate of retinaldegeneration in these mutant animals could be sensitive to the n-3 fattyacid content of retina.Methods: Beginning embryonic day 15, WT and heterozygous transgenicrats with P23H and S344ter rhodopsin mutations were fed semi-syntheticdiets enriched in n-6 (safflower oil, SO) or n-3 (flaxseed oil, FO)PUFA. At 35 and 55 days of age, electroretinographic (ERG) response,outer nuclear layer (ONL) thickness, and fatty acid composition ofplasma and ROS were determined. Student's t-tests and multivariateanalysis of variance with post hoc tests determined statisticaldifferences.Results: Rats fed FO or SO diets had different n-6/n-3 PUFA ratiosin plasma (1.3 and 62) and ROS (0.2 and 1.1, respectively). Althoughthere were profound effects of the diets on the plasma fatty acidcomposition, there were only minor differences between WT and transgenicanimals within each dietary regime. The ROS of FO fed rats had 70% more22:6n-3 than those fed SO, and the WT had higher concentrations of22:6n-3 than the transgenic animals (WT>P23H>S334ter). Incontrast, there was no difference in 22:6n-3 levels in ROS of WT andtransgenic rats fed the SO diet. At P55, both transgenic lines haddiminished ERGs and ONL thickness relative to the WT. There was nodetectable effect of ROS fatty acid enrichment on the rate of retinaldegeneration in the transgenic animals. However, the FO-diet provided amodest protection of function (b-wave) in S334ter animals.Conclusions: Feeding n-3 fatty acids to rats with mutant rhodopsintransgenes significantly increased the levels of 22:6n-3 in ROSmembranes, but had no effect on the rate of retinal degeneration.Therefore, the degeneration is not the result of low (or high) 22:6n-3in ROS and supplementation with 18:3n-3 will not rescue dyingphotoreceptor cells in these animal models of inherited retinaldegenerations.

[学科分类] 生物化学/生物物理