Cell Type-Selective Loss of Peroxisomal β-Oxidation Impairs Bipolar Cell but Not Photoreceptor Survival in the Retina

Daniëlle Swinkels,Stefan Vinckier,Eric Wever,Antoine H.C Van Kampen,Myriam Baes,Frédéric M Vaz,Yannick Das,Sai Kocherlakota

doi:10.3390/cells11010161

Abstract

Retinal degeneration is a common feature in peroxisomal disorders leading to blindness. Peroxisomes are present in the different cell types of the retina; however, their precise contribution to retinal integrity is still unclear. We previously showed that mice lacking the central peroxisomal β-oxidation enzyme, multifunctional protein 2 (MFP2), develop an early onset retinal decay including photoreceptor cell death. To decipher the function of peroxisomal β-oxidation in photoreceptors, we generated cell type selective Mfp2 knockout mice, using the Crx promotor targeting photoreceptors and bipolar cells. Surprisingly, Crx-Mfp2−/− mice maintained photoreceptor length and number until the age of 1 year. A negative electroretinogram was indicative of preserved photoreceptor phototransduction, but impaired downstream bipolar cell signaling from the age of 6 months. The photoreceptor ribbon synapse was affected, containing free-floating ribbons and vesicles with altered size and density. The bipolar cell interneurons sprouted into the ONL and died. Whereas docosahexaenoic acid levels were normal in the neural retina, levels of lipids containing very long chain polyunsaturated fatty acids were highly increased. Crx-Pex5−/− mice, in which all peroxisomal functions are inactivated in photoreceptors and bipolar cells, developed the same phenotype as Crx-Mfp2−/− mice. In conclusion, the early photoreceptor death in global Mfp2−/− mice is not driven cell autonomously. However, peroxisomal β-oxidation is essential for the integrity of photoreceptor ribbon synapses and of bipolar cells.

Highlights

Peroxisomes are involved in many processes, including reactive oxygen species (ROS) regulation, cellular stress response and antiviral defense [1,2]
Some staining was seen in interneuron cells, which most likely represents the bipolar cells, as it has been shown before that the cone-rod homeobox (Crx) promotor is active in these cells as well [25]
Our data prove that the early retinal phenotype observed in the global Mfp2−/− mice cannot be explained by the lack of peroxisomal β-oxidation in photoreceptors

Summary

Introduction

Peroxisomes are involved in many processes, including reactive oxygen species (ROS) regulation, cellular stress response and antiviral defense [1,2] They are highly metabolic active cell organelles and they have a crucial role in lipid metabolism via peroxisomal β-oxidation [1]. The potential importance of peroxisomal β-oxidation for the retina is further supported by the fact that it is involved in the metabolism of principal components of the retina It catabolizes various substrates, including very long chain polyunsaturated fatty acids (VLC-PUFAs). One cycle of peroxisomal β-oxidation is necessary to synthesize docosahexaenoic acid (DHA, C22:6n−3) [8] Both of these lipid species are highly enriched in the photoreceptor outer segments (POS), where they play a role in the phototransduction process [9,10,11,12,13]

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Results

Conclusion