The Rdcvf Signaling Is Linking Oxidative Stress to Neuroprotective Response

Abstract

Purpose: : The identification of the Rod-derived Cone Viability Factors RdCVF and RdCVF2 has paved the way for the treatment of patients suffering from retinitis pigmentosa by protecting cone photoreceptors cells and preventing central vision loss. The genes Nxnl1 and Nxnl2 encode for both a short protein isoform corresponding to the trophic factors and an additional longer isoform with extend homology to the family of thioredoxins, which are involved in the defense against oxidative stress. By analysis the RdCVF signaling and the phenotype of the mice with inactivation of the Nxnl1 or Nxnl2 genes we provide the rational for an integrated signaling coupling retinal insults to neuroprotective response.

Methods: : Functional assays in vivo were performed by delivering RdCVF by means of protein injections or AAV delivery, the cone rescue was evaluated by cone density measurement and ERG testing. RdCVF interacting proteins were indentified using a proteomic approach, and functionally validated. The phenotyping characterization of the retina in the Nxnl1-/- and Nxnl2-/- mice were studied using ERG testing and with the use of marker of oxidative stress.

Results: : We establish that RdCVF delivery in the eye of the P23H rat model of retinitis pigmentosa protects cone function to a higher extend than cone viability, suggesting a mechanism involving the maintenance of cone outer segments. This is related to the interaction of RdCVF with the microtubule associated protein Tau. Both the Nxnl1 and Nxnl2 knock-out mice show a progressive loss of cone function and density. That loss of function can be prevented by delivering RdCVF2 to the Nxnl2 -/- mouse. The visual phenotype is exacerbated by oxidative damage.

Conclusions: : Taking together our results demonstrate that the Nxnl1 and Nxnl2 genes are part of an endogenous signaling that is coupling the amount of oxidative stress to the function and the survival of cone photoreceptors.

Keywords: photoreceptors • retinal degenerations: cell biology • transgenics/knock-outs