Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice.

Yannick Das,Eric Wever,Sai Kocherlakota,Bokkyoo Jun,Myriam Baes,Lieve Moons,Nicolas G Bazan,Stefan Vinckier,Frédéric M Vaz,Paul P Van Veldhoven,Khanh V Do,Daniëlle Swinkels,Antoine H C Van Kampen

doi:10.3389/fcell.2021.632930

Abstract

Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain, however, elusive. Here, we report that mice with MFP2 inactivation display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, MFP2 deficient retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the mutant retinas revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, very long chain PUFAs were also reduced, with the exception of those containing ≥ 34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, our data reveal that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.

Highlights

Vision encompasses a well-orchestrated process that is initiated at the retina
Peroxisomal disorders are a group of inherited metabolic diseases that can be subdivided into two categories: peroxisome biogenesis disorders (PBD), of which Zellweger syndrome is the most severe, and single enzyme deficiencies (SED) (Waterham et al, 2016)
Upon comparison of the retinal morphology, gene expression and lipid composition, we observed no differences between Mfp2+/+ and Mfp2+/− mice, and, both genotypes were used as control for the Mfp2−/− mice

Summary

Introduction

Vision encompasses a well-orchestrated process that is initiated at the retina. To date, a plethora of mutations are recognized to cause developmental and degenerative retinal diseases. Peroxisomal disorders are a group of inherited metabolic diseases that can be subdivided into two categories: peroxisome biogenesis disorders (PBD), of which Zellweger syndrome is the most severe, and single enzyme deficiencies (SED) (Waterham et al, 2016). Mutations in the central enzyme of the peroxisomal β-oxidation pathway, the D-specific multifunctional protein 2 (MFP2) encoded by the HSD17B4 gene, cause a diverse spectrum of clinical disease presentations. The most severe clinical presentation is indistinguishable from Zellweger syndrome, characterized by general multi-organ dysfunction, and is mostly fatal within the first year of life. These patients often develop retinopathy with reduced electroretinography (ERG) responses (Ferdinandusse et al, 2006; Argyriou et al, 2016). Visual acuity was normal, these patients presented with abnormal retinal pigmentation, whether or not coinciding with abnormal ERG responses (McMillan et al, 2012; Lines et al, 2014; Amor et al, 2016)

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