Abstract
The large number of inherited retinal disease genes (IRD), including the photopigment rhodopsin and the photoreceptor outer segment (OS) structural component peripherin 2 (PRPH2), has prompted interest in identifying common cellular mechanisms involved in degeneration. Although metabolic dysregulation has been shown to play an important role in the progression of the disease etiology, identifying a common regulator that can preserve the metabolic ecosystem is needed for future development of neuroprotective treatments. Here, we investigated whether retbindin (RTBDN), a rod-specific protein with riboflavin binding capability, and a regulator of riboflavin-derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is protective to the retina in different IRD models; one carrying the P23H mutation in rhodopsin (which causes retinitis pigmentosa) and one carrying the Y141C mutation in Prph2 (which causes a blended cone-rod dystrophy). RTBDN levels are significantly upregulated in both the rhodopsin (Rho)P23H/+ and Prph2Y141C/+ retinas. Rod and cone structural and functional degeneration worsened in models lacking RTBDN. In addition, removing Rtbdn worsened other phenotypes, such as fundus flecking. Retinal flavin levels were reduced in RhoP23H/+/Rtbdn−/− and Prph2Y141C/+/Rtbdn−/− retinas. Overall, these findings suggest that RTBDN may play a protective role during retinal degenerations that occur at varying rates and due to varying disease mechanisms.
Highlights
Inherited retinal degenerations (IRD) comprise a group of widely varying, blinding retinal diseases caused by more than 300 different gene or loci mutations
We found that eliminating Rtbdn in the R172W Prph2 model of macular dystrophy [10] exacerbated Prph2-associated retinal disease, suggesting RTBDN may play a protective role in IRD [11]
Our overall findings are similar to what we previously reported when analyzing the effects of Rtbdn ablation in the Prph2R172W model
Summary
Inherited retinal degenerations (IRD) comprise a group of widely varying, blinding retinal diseases caused by more than 300 different gene or loci mutations (https://sph.uth.edu/retnet/disease.htm, accessed 19 October 2020). Over the past several decades, much work has been done to elucidate the mechanisms of disease for the most common retinal disease genes. As the number and diversity of genes responsible for IRD continues to increase, so has interest in identifying mechanisms of promoting photoreceptor homeostasis, which might be beneficial across multiple genes/mutations. Riboflavin (Vitamin B2) is a vitamin essential for cell growth and function [3]. It is primarily found in its redox active co-enzymatic forms, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). Consistent with the high level of metabolic activity in photoreceptors [5], retinal flavin levels are almost 20-fold higher than in blood [6,7]
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