The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

Abstract

Rod-derived cone viability factor (RdCVF) is a thioredoxin-like protein, which has therapeutic potential for rod-cone dystrophies such as retinitis pigmentosa (RP). Cone loss in rodent models of RP is effectively reduced by RdCVF treatment. In this study, we investigate the physiological role of RdCVF in the retina by analyzing the phenotype of the mouse lacking the RdCVF gene, Nxnl1. Although the mice do not show an obvious developmental defect, an age-related reduction of both cone and rod function and a delay in the dark-adaptation of the retina are recorded by electroretinogram (ERG). This functional change is accompanied by a 17% reduction in cone density and a 20% reduction in thickness of the outer nuclear layer. The transcriptome of the retina reveals early changes in the expression of genes involved in programmed cell death, stress-response and redox-signaling, which is followed by a generalized injury response with increased microglial activation, GFAP, FGF2 and lipid peroxidation levels. Furthermore, cones of the mice lacking Nxnl1 are more sensitive to oxidative stress with a reduction of 65% in the cone flicker ERG amplitude measured under hyperoxic conditions. We show here that the RdCVF gene, in addition to therapeutic properties, has an essential role in photoreceptor maintenance and resistance to retinal oxidative stress.

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

“…This protein is a member of the thioredoxin family, and has been shown to be protective against oxidative stress. [40][41][42] Mice with a targeted disruption of the rod-derived cone viability factor gene (Nxnl1À/À) show enhanced loss of cone photoreceptor viability and function, 43 and it has also been shown that sub-retinal inoculation of the purified protein results in a therapeutic effect. 44 In regard to the neuroprotective effect exerted by C1q in the current study, this protein is a primary component of the classical complement pathway.…”

Viral-mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration

“…RdCVF has been shown to mediate cone survival both in culture (9) and when injected subretinally into mouse and rat models of recessive and dominant forms of RP (5,10). Disruption of Nxnl1, the gene encoding RdCVF, renders mouse photoreceptors increasingly susceptible to photoreceptor dysfunction and cone loss over time (11).…”

Emerging Gene Therapies for Retinal Degenerations

“…Sahel and colleagues (Fintz et al, 2003;Léveillard et al, 2004) discovered a candidate for such a factor, RdCVF [rodderived cone viability factor; also named nucleoredoxin 1 (Nxn1)]. Characterization of a recent mouse knock-out for this gene showed that cones in the mutant are more susceptible to oxidative damage (Cronin et al, 2010). Interestingly, this gene has a domain with homology to thioredoxin, which has a role in establishing the redox state of cells through a thiol-oxydoreductase activity.…”