Restoration of Rod-Derived Metabolic and Redox Signaling to Prevent Blindness

Abstract

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 (NXNL1) gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The NXNL1 gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.