TY - JOUR
T1 - DHA Shortage Causes the Early Degeneration of Photoreceptors and RPE in Mice With Peroxisomal β-Oxidation Deficiency
AU - Swinkels, Daniëlle
AU - Kocherlakota, Sai
AU - Das, Yannick
AU - Dane, Adriaan D.
AU - Wever, Eric J. M.
AU - Vaz, Frédéric M.
AU - Bazan, Nicolas G.
AU - van Veldhoven, Paul P.
AU - Baes, Myriam
N1 - Funding Information: Supported by the Belgian Fund for Research in Ophthalmology, by KU Leuven (C14/18/088), and by the Research Foundation– Flanders (FWO G0A8619N). The Leica SP8X confocal micro- scope was provided by InfraMouse (KU Leuven-VIB) through a Hercules type 3 project (ZW09-03). Funding Information: The authors thank E. Nefyodova, B. Das, A. Carton, and A. Manderveld for the excellent technical assistance. Supported by the Belgian Fund for Research in Ophthalmology, by KU Leuven (C14/18/088), and by the Research Foundation–Flanders (FWO G0A8619N). The Leica SP8X confocal microscope was provided by InfraMouse (KU Leuven-VIB) through a Hercules type 3 project (ZW09-03). Publisher Copyright: Copyright 2023 The Authors.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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, develop retinopathy present with retinopathy. The representative mouse model lacking the central enzyme of this pathway, multifunctional protein 2 (Mfp2−/−), also show 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 and lactation and until sacrifice. Offspring were analyzed for retinal function via electroretinograms and 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 ages of 4, 8, and 16 weeks. RESULTS. DHA supplementation to Mfp2−/− mice restored retinal DHA levels and prevented photoreceptor shortening, death, and impaired functioning 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 a systemic supply of DHA is pivotal for the early retinal degeneration in Mfp2−/− mice. Furthermore, we report that adequate retinal DHA levels are essential not only for photoreceptors but also for RPE homeostasis.
AB - 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, develop retinopathy present with retinopathy. The representative mouse model lacking the central enzyme of this pathway, multifunctional protein 2 (Mfp2−/−), also show 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 and lactation and until sacrifice. Offspring were analyzed for retinal function via electroretinograms and 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 ages of 4, 8, and 16 weeks. RESULTS. DHA supplementation to Mfp2−/− mice restored retinal DHA levels and prevented photoreceptor shortening, death, and impaired functioning 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 a systemic supply of DHA is pivotal for the early retinal degeneration in Mfp2−/− mice. Furthermore, we report that adequate retinal DHA levels are essential not only for photoreceptors but also for RPE homeostasis.
KW - DHA
KW - RPE
KW - VLC-PUFA
KW - neuroprotection
KW - peroxisome
UR - http://www.scopus.com/inward/record.url?scp=85176424542&partnerID=8YFLogxK
U2 - https://doi.org/10.1167/iovs.64.14.10
DO - https://doi.org/10.1167/iovs.64.14.10
M3 - Article
C2 - 37934161
SN - 0146-0404
VL - 64
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 14
M1 - 10
ER -