Retinitis pigmentosa causes the death of cone cells, leading to blindness. A factor secreted from rod cells, RdCVF, promotes cone survival in a mouse model of the disease. It now emerges that RdCVF works by increasing glucose uptake in cones.
In daylight, light-sensing photoreceptor cells called cones endow us with rich, high-acuity colour vision. By contrast, their night-time counterparts, rod cells, are so light-sensitive that they enable us to see when walking in the woods under starlight. Sadly, a mutation in any one of more than 200 genes can cause diseases such as retinitis pigmentosa that bring about photoreceptor degeneration and lead to blindness1,2. Many of these disease-causing genes are rod-specific, affecting only night vision, but when rods die, the malfunction and death of cones soon follows. Writing in Cell, Aït-Ali et al.3 provide evidence for an interaction between these two cell types that might explain why cones depend on rods for their survival, and that might eventually lead to a therapy for such diseases.
Retinitis pigmentosa affects 1 in 3,000 people2, and effective treatments are sorely needed. The large number of disease-causing mutations means that these treatments should be gene-independent, focusing instead on targeting the biological pathways that cause the cones' death. The reasons for their death are unclear. However, there is evidence that several factors can contribute to cone death in retinitis pigmentosa. These include hyperoxia (an excess of oxygen), which causes oxidative damage by increasing the levels of free radicals4,5,6; a lack of energy7; and a lack of intermediates in the anabolic processes by which large molecules are constructed from smaller ones7.
In agreement with a role for such factors, hyperactivation of the protein complex mTOR1, which controls cell metabolism by balancing demand with supply, increases cone survival8. This protein complex probably acts by promoting the expression of genes that improve glucose uptake and use, raising levels of anabolic intermediates and of an anabolic cofactor molecule called NADPH. Adequate levels of NADPH are likely to be crucial to cone survival because, in addition to its role in anabolic processes, it is needed for pathways that detoxify free radicals in hyperoxic retinas. Injection of antioxidants4 or viral-vector delivery of genes that fight oxidation6 prolong cone survival in mouse models of retinitis pigmentosa, supporting the theory that oxidation is a cause of cone death.
Healthy photoreceptors are metabolically very active9, and so require high levels of glucose, which is delivered from the bloodstream through retinal pigmented epithelial cells. Because NADPH is produced by the oxidation of glucose, the demand for glucose in hyperoxic conditions is likely to be exceptionally high. A glucose transporter protein called Glut-1, located on the cell surface, mediates glucose uptake by photoreceptors, and evidence suggests7 that a failure to take up sufficient glucose might contribute to cone death in retinitis pigmentosa. But there is a puzzling aspect to this model — glucose is delivered to the retina at a high rate and, after the death of rods, cones should have access to higher than normal levels of glucose. This suggests that there must be an added level of complexity underlying glucose uptake in cones.
Another factor that supports cone-cell survival10 is a protein secreted from rods, called rod-derived cone viability factor (RdCVF)11, that may have antioxidant activity. The cones of mice lacking RdCVF are more susceptible to oxidative damage than those of controls, and these mice show reduced photoreceptor activity with ageing12. Aït-Ali et al. therefore set out to explore the mechanism by which RdCVF promotes cone-cell survival. Using mass spectrometry, they identified a protein, called Basigin-1, that binds to RdCVF. Basigin-1 is found on the surface of cones and is known13 to cause retinitis pigmentosa when mutated in mice. The authors also identified Glut-1 as a Basigin-1-binding protein. But a previous study showed that, contrary to what might have been expected, loss of Basigin-1 did not affect the expression of Glut-1 or, for the most part, its distribution in the retina14.
Aït-Ali and colleagues observed that addition of RdCVF increased glucose uptake, lactate release and ATP production in photoreceptor cells in vitro — three cellular responses suggesting that RdCVF increases metabolic flux. Furthermore, the authors found that a decrease in levels of Basigin-1 and Glut-1 eliminated the ability of RdCVF to promote photoreceptor survival. The authors propose that RdCVF, Basigin-1 and Glut-1 form a complex at the cell surface that increases glucose uptake (Fig. 1). However, the level of Glut-1 on the cell surface did not increase after RdCVF addition, leading the researchers to suggest that this complex instead acts to increase levels of the active form of Glut-1. Future work should test this model. It will also be of interest to study the potential antioxidant role of RdCVF, together with the formation and activity of this three-protein complex, which might, as Aït-Ali et al. suggest, depend on a redox-sensitive interaction between RdCVF and Basigin-1.
A study published earlier this year showed that the delivery of RdCVF in mice with retinitis pigmentosa using an adeno-associated virus (AAV) prolonged cone survival and function15. AAV is a safe and effective vector that is used for ocular gene therapy in humans16, and this, together with Aït-Ali and colleagues' finding that Basigin-1 is expressed in human retinas, suggests that AAV–RdCVF might be an effective way to treat many types of photoreceptor disease. Owing to the large number of disease genes that cause blindness in humans, a treatment that could promote the survival of cones in a gene-independent manner would be a welcome prospect.
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Journal of Clinical Investigation (2016)