Thioredoxin rod-derived cone viability factor protects against photooxidative retinal damage

Abstract

Rod-derived cone viability factor (RdCVF) is a trophic factor of the thioredoxins family that promotes the survival of cone photoreceptors. It is encoded by the nucleoredoxin-like gene 1 Nxnl1 which also encodes by alternative splicing a long form of RdCVF (RdCVFL), a thioredoxin enzyme that interacts with TAU. The known role of thioredoxins in the defense mechanism against oxidative damage led us to examine the retinal phenotype of the Nxnl1(-/-) mice exposed to photooxidative stress. Here we found that, in contrast to wild-type mice, the rod photoreceptors of Nxnl1(-/-) mice are more sensitive to light after exposure to 1700 or 2500 lx. The delivery of RdCVF by AAV to mice deficient of Nxnl1(-/-) protects rod photoreceptors from light damage. Interestingly, the RdCVF2L protein, encoded by the paralog gene Nxnl2, is able to reduce TAU phosphorylation, as does RdCVFL, but does not protect the rod from light damage. Our result shows that the Nxnl1 gene, through the thioredoxin RdCVFL, is part of an endogenous defense mechanism against photooxidative stress that is likely of great importance for human vision.

Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis

“…RdCVF, a truncated thioredoxin-like protein lacking thioloxidoreductase activity, was identified by high content screening of a mouse retinal cDNA library on cone-enriched cultures from chicken embryos (Lé veillard et al, 2004). RdCVF is an alternative splice variant of the nucleoredoxin-like 1 (Nxnl1) gene, whose other splice product is RdCVFL, an active thioredoxin that protects its binding partner, the microtubule associated protein TAU, from oxidation and aggregation (Elachouri et al, 2015;Fridlich et al, 2009). Nxnl1 À/À mice experience an age-dependent loss of rod and cone function and cone degeneration.…”

Pharmacological approaches to retinitis pigmentosa: A laboratory perspective

“…This encodes for two products via alternative splicing, a truncated thioredoxin-like protein and the full-length protein, capable of enzymatic activity. The molecule provided exogenously, by intravitreal injection, protects photoreceptor cells in RP mutant mice (Cronin et al, 2010;Elachouri et al, 2015). Conversely, mutants missing RdCVF undergo a progressive photoreceptor loss.…”

Photo-damage, photo-protection and age-related macular degeneration

“…Nevertheless, since they depend on the rod-derived cone viability factor (RdCVF) 116 , they would disappear after demise of parafoveal rods. It has been demonstrated that RdCVF protects 661W cells from photooxidative damage 117 and, most important, that RdCVFdeficient mice are extraordinarily sensitive to light-induced damage 118 .…”