Abstract
Purpose :
Patients with peroxisome biogenesis disorders or a deficiency in peroxisomal β-oxidation often present with retinopathy. This pathway is involved in the metabolism of very long chain and poly-unsaturated fatty acids that are enriched in the photoreceptor outer segments (POS). Although extensively studied in liver, little is known about the importance of peroxisomal β-oxidation in the retina.
Methods :
We characterized the retinal pathology in a previously developed mouse model with deficient peroxisomal β-oxidation due to lack of the D-specific multifunctional protein 2, encoded by Hsd17b4 (MFP2 knockout), using functional, structural and metabolic analyses.
Results :
ERG analysis revealed impaired retinal function in 3-week-old and 8-week-old MFP2 knockout mice, which resulted in impaired visual acuity. This was accompanied by several histological anomalies: i) POS length was already reduced at eye opening (P14) and remained shortened into adulthood, although disc morphogenesis did not seem to be disturbed, ii) progressive photoreceptor degeneration, iii) from the age of 6 weeks retinal pigment epithelial (RPE) cells protruded into the POS layer and showed progressive loss of the typical honeycomb pattern. As docosahexaenoic acid (DHA, C22:6n-3) is thought to be of pivotal importance for POS synthesis and maintenance, and peroxisomes are involved in its metabolism, lipid analyses were performed. Total retinal DHA was decreased, which was accompanied by a compensatory increase in n-6 fatty acids, despite unaltered DHA levels in the plasma. The morphological changes of the RPE were accompanied with reduced functionality as revealed by a severe reduction of visual cycle gene expression and reduced levels of retinol.
Conclusions :
Our data prove that peroxisomal β-oxidation is essential for the preservation of both photoreceptors and RPE cells. Data of ongoing transcriptome and lipidome analyses will be presented, which should provide leads to decipher the mechanisms underlying the retinal degeneration.
This is a 2020 ARVO Annual Meeting abstract.