DHA does not protect ELOVL4 transgenic mice from retinal degeneration.
OBJECTIVE
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.
Li
Feng
F
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Marchette
Lea D
LD
Brush
Richard S
RS
Elliott
Michael H
MH
Le
Yun-Zheng
YZ
Henry
Kimberly A
KA
Anderson
Ashley G
AG
Zhao
Chao
C
Sun
Xufang
X
Zhang
Kang
K
Anderson
Robert E
RE
D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000032:analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012160:Retina / Q000737:chemistry / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D012243:Rhodopsin / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; C418975:ELOVL4 protein, human; D005136:Eye Proteins; D005227:Fatty Acids; D008565:Membrane Proteins; C466741:fat-1 protein, C elegans; D004281:Docosahexaenoic Acids; D012243:Rhodopsin; D044943:Fatty Acid Desaturases