Abstract
Purpose Patients deficient in peroxisomal β-oxidation, which is essential for the synthesis of docosahexaenoic acid (DHA, C22:6n-3) and breakdown of very long-chain polyunsaturated fatty acids (VLC-PUFAs), both important components of photoreceptor outer segments, present with retinopathy. The representative mouse model lacking the central enzyme of this pathway, multifunctional protein 2 (Mfp2−/−), also develops early onset retinal decay and cell-autonomous retinal pigment epithelium (RPE) degeneration, accompanied by reduced plasma and retinal DHA levels. In this study, we investigated whether DHA supplementation can rescue the retinal degeneration of Mfp2−/− mice.
Methods Mfp2+/− breeding pairs and their offspring were fed a 0.12% DHA or control diet during gestation, lactation and until sacrifice. Offspring were analysed for retinal function via electroretinograms, for lipid composition of neural retina and plasma with lipidome analysis and gas chromatography respectively, and histologically using retinal sections and RPE flatmounts at the age of 4, 8 and 16 weeks.
Results DHA supplementation to Mfp2−/− mice restored retinal DHA levels and prevented photoreceptor shortening, impaired functioning and death until 8 weeks. In addition, rescue of retinal DHA levels temporarily improved the ability of the RPE to phagocytose outer segments and delayed the RPE dedifferentiation. However, despite the initial rescue of retinal integrity, DHA supplementation could not prevent retinal degeneration at 16 weeks.
Conclusions We reveal that the shortage of systemic supply of DHA is pivotal for the early retinal degeneration in Mfp2−/− mice. Furthermore, we unveil that adequate retinal DHA levels are essential for both photoreceptor and RPE homeostasis.
Competing Interest Statement
The authors have declared no competing interest.