Abstract
Purpose :
Retinitis pigmentosa (RP) is a retinal degenerative disease characterized by the progressive loss of photoreceptors. It affects more than 1 million people worldwide. Despite the genetic heterogeneity, one common phenomenon is shared in RP that the death of rods always precedes the death of cones. The mystery was solved by the discovery of rod-derived cone viability factor (RdCVF) encoded by NXNL1 gene acting as a tropic factor secreted by rods to promote the utilization of glucose by cones, thus sustaining the survival of cones. Interestingly, NXNL1 encodes two proteins due to alternative splicing, the short form RdCVF, and the long-form RdCVFL with a typical thioredoxin (TXN)-like structure. It has been shown by our group that adeno-associated virus (AAV)-mediated expression of RdCVF and RdCVFL could be a potential gene therapy of RP. The short protein, RdCVF, has been well-studied, however, the mechanism of action of RdCVFL remains unclear.
Methods :
The RdCVFL was recombinantly purified. Then the biochemical property of RdCVFL as a TXN-like protein was examined by coupling the two major antioxidant systems, the TXN system and the glutathione (GSH) system. The chaperone activity of RdCVFL was also examed.
Results :
RdCVFL can be reduced by TXN and GSH systems, and the reduced RdCVFL exhibited an S-denitrosylase activity. However, it is not a highly selective substrate of both systems, showing little activity to reduce cystine, oxidized-GSH, and S-glutathionylated proteins. Interestingly, RdCVFL exhibited a prominent chaperone activity in thermal aggregation assays.
Conclusions :
RdCVFL, as a TXN-like protein, may participate in antioxidant defense and redox signaling regulation in the retina. In addition, its chaperone activity may contribute to protein quality control during outer segment renewal or in the prevention of aggregation of the microtubule protein τ (TAU).
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.