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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&minus, /&minus, and Prph2Y141C/+/Rtbdn&minus, 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.

Peripherin 2 (Prph2) is a photoreceptor-specific tetraspanin protein present in the outer segment (OS) rims of rod and cone photoreceptors. It shares many common features with other tetraspanins, including a large intradiscal loop which contains several cysteines. This loop enables Prph2 to associate with itself to form homo-oligomers or with its homologue, rod outer segment membrane protein 1 (Rom1) to form hetero-tetramers and hetero-octamers. Mutations in PRPH2 cause a multitude of retinal diseases including autosomal dominant retinitis pigmentosa (RP) or cone dominant macular dystrophies. The importance of Prph2 for photoreceptor development, maintenance and function is underscored by the fact that its absence results in a failure to initialize OS formation in rods and formation of severely disorganized OS membranous structures in cones. Although the exact role of Rom1 has not been well studied, it has been concluded that it is not necessary for disc morphogenesis but is required for fine tuning OS disc size and structure. Pathogenic mutations in PRPH2 often result in complex and multifactorial phenotypes, involving not just photoreceptors, as has historically been reasoned, but also secondary effects on the retinal pigment epithelium (RPE) and retinal/choroidal vasculature. The ability of Prph2 to form complexes was identified as a key requirement for the development and maintenance of OS structure and function. Studies using mouse models of pathogenic Prph2 mutations established a connection between changes in complex formation and disease phenotypes. Although progress has been made in the development of therapeutic approaches for retinal diseases in general, the highly complex interplay of functions mediated by Prph2 and the precise regulation of these complexes made it difficult, thus far, to develop a suitable Prph2-specific therapy. Here we describe the latest results obtained in Prph2-associated research and how mouse models provided new insights into the pathogenesis of its related diseases. Furthermore, we give an overview on the current status of the development of therapeutic solutions.