RORα deficiency leads to aged-related retinal degeneration in mice

Abstract

Purpose : The lipid-cholesterol metabolic pathway is implicated in the pathogenesis of age-related macular degeneration (AMD), a leading, incurable cause of vision loss in the elderly. Retinoic acid receptor-related orphan receptor alpha (RORα), a lipid-sensing nuclear receptor that functions as a ligand-dependent transcriptional regulator, mediates gene expression in many physiological processes, such as lipid metabolism and immunity. The transcriptional activity of RORα is mainly modulated by cholesterol and its derivatives, which are enriched in drusen—the hallmark of AMD. Here, we investigated the role of RORα in the regulation of age-dependent retinal/retinal pigment epithelial (RPE) degeneration in mice genetically deficient in RORα (Rora^Sg/Sg).

Methods : Mice with spontaneous RORα deficiency (Rora^Sg/Sg) and littermate wild type (WT) controls were analyzed at various time points during aging. Morphological features were captured with en face and optical coherence tomographic fundus images in vivo and in isolated RPE/choroid complex flat mounts and cross-sections from enucleated eyes. Visual function was measured by electroretinography (ERG). Expression levels of Rora and relevant metabolic and inflammatory genes were analyzed in retinas and RPE/choroid complexes isolated from Rora^Sg/Sg and WT mice.

Results : RORα was expressed in both retinas and RPE/choroid complexes in WT eyes. Deficiency of RORα in aged mouse eyes caused increased number of abnormal whitish yellow lesions in the fundus starting from 6-7 months old, with areas of reticular pigmentary degeneration. At 9 month, Rora^Sg/Sg mice showed ~8-fold increase in lesion count compared with WT. Significant disruption of bipolar cell morphology appeared in aged Rora^Sg/Sg retina cross sections. Correspondingly, we observed substantial decreases in ERG b-wave amplitudes, consistent with deficits in visual function. Additionally, in RPE/Choroid flat mounts and cross-sections, aged Rora^Sg/Sg mice exhibited drastically increased number of microglia/macrophages with more activated morphology. Rora^Sg/Sg retinas and RPE/choroid complexes both showed upregulation of immune- and inflammation-related genes, consistent with the increased number of microglia/macrophages.

Conclusions : Together these findings suggest that genetic deficiency RORα causes retina and RPE degeneration during aging and that RORα is a novel transcriptional regulator of age-dependent retina/RPE dysfunction.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.