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DHA does not protect ELOVL4 transgenic mice from retinal degeneration.

Li F, Marchette LD, Brush RS, Elliott MH, Le YZ, Henry KA, Anderson AG, Zhao C, Sun X, Zhang K, Anderson RE - Mol. Vis. (2009)

Bottom Line: There was no effect of retinal fatty acids on the rate of degeneration of retinas expressing the ELOVL4 transgene.We found no evidence that high levels of DHA in retinal membranes protected photoreceptor cells expressing mutant ELOVL4 from retinal degeneration.We conclude that DHA is not beneficial for the treatment of retinal degeneration in this animal model of human STGD3 macular dystrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

ABSTRACT

Purpose: Dominant Stargardt macular dystrophy (STGD3) is caused by several different mutations in a gene named ELOVL4, which shares sequence homologies with a family of genes that encode proteins involved in the ELOngation of Very Long chain fatty acids. Studies have suggested that patients with STGD3 have aberrant metabolism of docosahexaenoic acid (DHA, 22:6n3), the major polyunsaturated fatty acid (PUFA) in retinal rod outer segment membranes. We tested the effect of DHA on the progression of retinal degeneration in transgenic mice that express one of the mutations identified in STGD3.

Methods: Transgenic mice expressing mutant human ELOVL4 (TG2) were bred to mice expressing the fat-1 protein, which can convert n6 to n3 PUFA. Mice were maintained on an n3-deficient diet containing 10% safflower oil (SFO, enriched in n6 PUFA; n6/n3=273) so that four experimental groups were produced that differed only in levels of n3 PUFA and expression of the hELOVL4 transgene. These groups were identified by genotyping and named Fat1+/TG2+, Fat1(-)/TG2+, Fat1+/TG2(-), and Fat1(-)/TG2(-). All were continued on the SFO diet for 4 to 16 weeks such that those not expressing Fat1 would be deficient in n3 fatty acids. At both time points, animals were analyzed for retinal function by electroretinography (ERG), photoreceptor cell viability by outer nuclear layer (ONL) thickness measurements, fatty acid profiles in several tissues, and rhodopsin levels.

Results: Mice expressing the fat-1 transgene had significantly higher levels of n3 PUFA, primarily DHA, in retina, liver, and plasma lipids at 4 and 16 weeks of age. Retinal DHA levels in fat-1 mice were twice those of controls. By 16 weeks of age, mice expressing the mutant hELOVL4 transgene had a significantly greater loss of photoreceptor cells, reduced ERG amplitudes, and lower rhodopsin levels than control mice. There was no effect of retinal fatty acids on the rate of degeneration of retinas expressing the ELOVL4 transgene.

Conclusions: We found no evidence that high levels of DHA in retinal membranes protected photoreceptor cells expressing mutant ELOVL4 from retinal degeneration. We conclude that DHA is not beneficial for the treatment of retinal degeneration in this animal model of human STGD3 macular dystrophy.

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Quantification of morphologic changes in transgenic mice. Measurements of ONL thickness (±SD) were made along the vertical meridian of the eye in Fat1+/TG2+, Fat1–/TG2+, Fat1+/TG2–, and Fat1–/TG2– mice maintained in 20 lx cyclic light (n≥8). A, C: Averages were made of ≥8 retinas of transgenic mice at 4 and 16 weeks of age. B, D: The histograms are the average ONL thickness at both age groups.
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f5: Quantification of morphologic changes in transgenic mice. Measurements of ONL thickness (±SD) were made along the vertical meridian of the eye in Fat1+/TG2+, Fat1–/TG2+, Fat1+/TG2–, and Fat1–/TG2– mice maintained in 20 lx cyclic light (n≥8). A, C: Averages were made of ≥8 retinas of transgenic mice at 4 and 16 weeks of age. B, D: The histograms are the average ONL thickness at both age groups.

Mentions: Quantification of age-related loss of rod photoreceptors at each point measured along the vertical meridian is presented in the “spider” graphs in Figure 5A,C. Photoreceptor nuclei were lost in both inferior and superior regions of the mice expressing the ELOVL4 transgene compared to controls, especially at 16 weeks of age. Mean ONL thicknesses taken from 14 sites along the vertical meridian (7 superior and 7 inferior of the optic nerve head) were calculated for both age groups. There were no significant differences in ONL thickness between F+/T+ versus F–/T+ and F+/T– versus F–/T– mice at 4 and 16 weeks of age. However, compared to 4-week-old T+ mice (Figure 5B), ONL thickness was reduced 31% in F+ mice and 32% in F– mice at 16 weeks of age (Figure 5D).


DHA does not protect ELOVL4 transgenic mice from retinal degeneration.

Li F, Marchette LD, Brush RS, Elliott MH, Le YZ, Henry KA, Anderson AG, Zhao C, Sun X, Zhang K, Anderson RE - Mol. Vis. (2009)

Quantification of morphologic changes in transgenic mice. Measurements of ONL thickness (±SD) were made along the vertical meridian of the eye in Fat1+/TG2+, Fat1–/TG2+, Fat1+/TG2–, and Fat1–/TG2– mice maintained in 20 lx cyclic light (n≥8). A, C: Averages were made of ≥8 retinas of transgenic mice at 4 and 16 weeks of age. B, D: The histograms are the average ONL thickness at both age groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2697457&req=5

f5: Quantification of morphologic changes in transgenic mice. Measurements of ONL thickness (±SD) were made along the vertical meridian of the eye in Fat1+/TG2+, Fat1–/TG2+, Fat1+/TG2–, and Fat1–/TG2– mice maintained in 20 lx cyclic light (n≥8). A, C: Averages were made of ≥8 retinas of transgenic mice at 4 and 16 weeks of age. B, D: The histograms are the average ONL thickness at both age groups.
Mentions: Quantification of age-related loss of rod photoreceptors at each point measured along the vertical meridian is presented in the “spider” graphs in Figure 5A,C. Photoreceptor nuclei were lost in both inferior and superior regions of the mice expressing the ELOVL4 transgene compared to controls, especially at 16 weeks of age. Mean ONL thicknesses taken from 14 sites along the vertical meridian (7 superior and 7 inferior of the optic nerve head) were calculated for both age groups. There were no significant differences in ONL thickness between F+/T+ versus F–/T+ and F+/T– versus F–/T– mice at 4 and 16 weeks of age. However, compared to 4-week-old T+ mice (Figure 5B), ONL thickness was reduced 31% in F+ mice and 32% in F– mice at 16 weeks of age (Figure 5D).

Bottom Line: There was no effect of retinal fatty acids on the rate of degeneration of retinas expressing the ELOVL4 transgene.We found no evidence that high levels of DHA in retinal membranes protected photoreceptor cells expressing mutant ELOVL4 from retinal degeneration.We conclude that DHA is not beneficial for the treatment of retinal degeneration in this animal model of human STGD3 macular dystrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

ABSTRACT

Purpose: Dominant Stargardt macular dystrophy (STGD3) is caused by several different mutations in a gene named ELOVL4, which shares sequence homologies with a family of genes that encode proteins involved in the ELOngation of Very Long chain fatty acids. Studies have suggested that patients with STGD3 have aberrant metabolism of docosahexaenoic acid (DHA, 22:6n3), the major polyunsaturated fatty acid (PUFA) in retinal rod outer segment membranes. We tested the effect of DHA on the progression of retinal degeneration in transgenic mice that express one of the mutations identified in STGD3.

Methods: Transgenic mice expressing mutant human ELOVL4 (TG2) were bred to mice expressing the fat-1 protein, which can convert n6 to n3 PUFA. Mice were maintained on an n3-deficient diet containing 10% safflower oil (SFO, enriched in n6 PUFA; n6/n3=273) so that four experimental groups were produced that differed only in levels of n3 PUFA and expression of the hELOVL4 transgene. These groups were identified by genotyping and named Fat1+/TG2+, Fat1(-)/TG2+, Fat1+/TG2(-), and Fat1(-)/TG2(-). All were continued on the SFO diet for 4 to 16 weeks such that those not expressing Fat1 would be deficient in n3 fatty acids. At both time points, animals were analyzed for retinal function by electroretinography (ERG), photoreceptor cell viability by outer nuclear layer (ONL) thickness measurements, fatty acid profiles in several tissues, and rhodopsin levels.

Results: Mice expressing the fat-1 transgene had significantly higher levels of n3 PUFA, primarily DHA, in retina, liver, and plasma lipids at 4 and 16 weeks of age. Retinal DHA levels in fat-1 mice were twice those of controls. By 16 weeks of age, mice expressing the mutant hELOVL4 transgene had a significantly greater loss of photoreceptor cells, reduced ERG amplitudes, and lower rhodopsin levels than control mice. There was no effect of retinal fatty acids on the rate of degeneration of retinas expressing the ELOVL4 transgene.

Conclusions: We found no evidence that high levels of DHA in retinal membranes protected photoreceptor cells expressing mutant ELOVL4 from retinal degeneration. We conclude that DHA is not beneficial for the treatment of retinal degeneration in this animal model of human STGD3 macular dystrophy.

Show MeSH
Related in: MedlinePlus