Elimination of a Retinal Riboflavin Binding Protein Exacerbates Degeneration in a Model of Cone-Rod Dystrophy

PURPOSE: Riboflavin and its cofactors are essential for cellular energy generation, responses to oxidative stress, and overall homeostasis. Retbindin is a novel retina-specific riboflavin binding protein essential for the maintenance of retinal flavin levels, but its function remains poorly understood. To further elucidate the function of retbindin in retinal health and disease, we evaluated its role in retinal degeneration in a cone-rod dystrophy model associated with the R172W mutation in the photoreceptor tetraspanin Prph2. METHODS: We performed structural, functional, and biochemical characterization of R172W-Prph2 mice with and without retbindin (Rtbdn(−)(/)(−)/Prph2(R172W)). RESULTS: Retbindin is significantly upregulated during degeneration in the R172W model, suggesting that retbindin plays a protective role in retinal degenerative diseases. This hypothesis was supported by our findings that R172W mice lacking retbindin (Rtbdn(−)(/)(−)/Prph2(R172W)) exhibit functional and structural defects in rods and cones that are significantly worse than in controls. Retinal flavin levels were also altered in the Rtbdn(−)(/)(−)/Prph2(R172W) retina. However, in contrast to the Rtbdn(−)(/)(−) retina which has reduced flavin levels compared to wild-type, Rtbdn(−)(/)(−)/Prph2(R172W) retinas exhibited elevated levels of riboflavin and the flavin cofactor FMN. CONCLUSIONS: These results indicate that retbindin plays a protective role during retinal degeneration, but that its function is more complex than previously thought, and suggest a possible role for retbindin in protecting the retina from phototoxicity associated with unbound flavins. This study highlights the essential role of precisely regulated homeostatic mechanisms in photoreceptors, and shows that disruption of this metabolic balance can contribute to the degenerative process associated with other cellular defects.