High levels of retinal docosahexaenoic acid do not protect photoreceptor degeneration in VPP transgenic mice

[摘要] Purpose: To determine whetherdocosahexaenoic acid can protect against hereditary retinaldegenerations in transgenic mice expressing the V20G, P23H, and P27L(VPP) rhodopsin mutations. Methods: Female transgenic miceexpressing the VPP rhodopsin mutation, known to cause a retinaldegeneration, were bred to male transgenic mice expressing the fat-1gene, which can convert n6 to n3 polyunsaturated fatty acids (PUFA).Several weeks before breeding, the female mice were fed a standard dietcontaining 10% safflower oil (SFO), which is high in n6 and low in n3PUFA (n6/n3=273). Offspring were genotyped and four groups identified:Fat1+/VPP+, Fat1–/VPP+, Fat1+/VPP–,andFat1–/VPP–. Dams were maintained on the SFOdiet during the nursing period and offspring were kept on the SFO dietafter weaning. At 4, 16, and 28 weeks of age, retinal function wasevaluated by electroretinography (ERG), photoreceptor cell loss wasquantified by measuring outer nuclear layer thickness, and rhodopsinlevels were determined. Fatty acid profiles were analyzed in wholeretina, plasma, and liver at 4 and 28 weeks of age. Results: Expression of fat-1 inthe absence of dietary n3 PUFA led to the generation of two groups ofmice with distinctly different levels of n3 and n6 PUFA in the threetissues that were analyzed. Already at four weeks of age, the retinasof fat-1 positive animals had higher levels of n3 PUFA thantheir wild-type counterparts (23%–29% versus 6.4%–6.5%). In addition,by four weeks of age, there was a significant loss of rod photoreceptorcells in the VPP mice. Progression of retinal degeneration occurredwith increasing age in VPP positive mice, with photoreceptorcell death occurring in both inferior and superior regions. Amplitudesof the a- and b-waves of the ERG were significantly reduced with age,with VPP positive mice showing the greatest change. Rhodopsincontent was lower in the VPP transgenic mice. There were no significantdifferences in outer nuclear layer thickness or ERG amplitudes betweenFat1+/VPP+ and Fat1–/VPP+,or between Fat1+/VPP–and Fat1–/VPP–mice at any of the three ages. Conclusions: High levels of retinaldocosahexaenoic acid do not protect mice expressing the VPP rhodopsinmutation from retinal degeneration.

[学科分类] 生物化学/生物物理