Rods Feed Cones to Keep them Alive
2015; Cell Press; Volume: 161; Issue: 4 Linguagem: Inglês
10.1016/j.cell.2015.04.031
ISSN1097-4172
Autores Tópico(s)Neural dynamics and brain function
ResumoCone photoreceptors, responsible for high-resolution and color vision, progressively degenerate following the death of rod photoreceptors in the blinding disease retinitis pigmentosa. Aït-Ali et al. describe a molecular mechanism by which RdCVF, a factor normally released by rods, controls glucose entry into cones, enhancing their survival. Cone photoreceptors, responsible for high-resolution and color vision, progressively degenerate following the death of rod photoreceptors in the blinding disease retinitis pigmentosa. Aït-Ali et al. describe a molecular mechanism by which RdCVF, a factor normally released by rods, controls glucose entry into cones, enhancing their survival. The retina is a highly sophisticated biological computer that captures an image with its photoreceptors and extracts different visual features to describe the visual scene to higher brain centers in simple and compact terms. Although photoreceptors, the rods and cones, are only two out of the sixty retinal cell types, they are exceptionally important: all image-forming vision depends on their proper function. Despite the fact that rods outnumber cones 20 to 1, human vision is mostly based on cones. Rods are distributed at the periphery of the retina and are the photosensors for low light levels. Cones are concentrated in the center of the retina and work at higher light levels. Since cones are necessary for the high-resolution color vision that enables us to read, recognize faces, and enjoy the colorful world, in the modern world we surround ourselves with enough light to turn on the cones. Most of us spend little time in conditions where photons are scarce and, therefore, our dependence on rod function is minor. A study presented in this issue of Cell offers key insight into the interdependence of rods and cones, and how it is disrupted in the genetic disorder retinitis pigmentosa (Aït-Ali et al., 2015Aït-Ali N. Fridlich R. Millet-Puel G. Clérin E. Delalande F. Jaillard C. Blond F. Perrocheau L. Reichman S. Byrne L.C. et al.Cell. 2015; 161 (this issue): 817-832Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). The genes involved in retinitis pigmentosa are primarily expressed only in rods and are important for their function (Hartong et al., 2006Hartong D.T. Berson E.L. Dryja T.P. Lancet. 2006; 368: 1795-1809Abstract Full Text Full Text PDF PubMed Scopus (2277) Google Scholar). If humans rely mostly on cone vision, why is this disease so severe? The reason stems from the fact that rods and cones are dependent on each other. When rods are dysfunctional but alive, as in another genetic disease called stationary night blindness, cones are functional. Indeed, patients with stationary night blindness are capable of living an almost normal life. However, when rods die, as happens in retinitis pigmentosa, cones sense this loss and react to it. This reaction is devastating. First, cones lose their outer segments, which serve as light detectors, causing patients to become blind. Second, on a longer timescale, the other parts of the cones progressively degenerate. Due to the importance of cones for human vision, and their dependence on rods, two fundamental questions in retinitis pigmentosa research are why and how do cones react to rod death and how can we prevent cones from degenerating?. There have been several important insights in recent years. One of these insights, originating in José-Alain Sahel's laboratory, came from the logic that if rods are necessary for cone survival, rods may release a factor that enhances cone survival (Mohand-Said et al., 1998Mohand-Said S. Deudon-Combe A. Hicks D. Simonutti M. Forster V. Fintz A.C. Léveillard T. Dreyfus H. Sahel J.A. Proc. Natl. Acad. Sci. USA. 1998; 95: 8357-8362Crossref PubMed Scopus (171) Google Scholar). Indeed, such a molecule, named rod-derived cone viability factor (RdCVF) has been identified by Thierry Léveillard and José-Alain Sahel (Léveillard et al., 2004Léveillard T. Mohand-Saïd S. Lorentz O. Hicks D. Fintz A.-C. Clérin E. Simonutti M. Forster V. Cavusoglu N. Chalmel F. et al.Nat. Genet. 2004; 36: 755-759Crossref PubMed Scopus (338) Google Scholar). It has been shown that, after rods die, the resulting loss of RdCVF production contributes to cone degeneration, and that externally supplied RdCVF slows down this process (Byrne et al., 2015Byrne L.C. Dalkara D. Luna G. Fisher S.K. Clérin E. Sahel J.-A. Léveillard T. Flannery J.G. J. Clin. Invest. 2015; 125: 105-116Crossref PubMed Scopus (107) Google Scholar, Léveillard and Sahel, 2010Léveillard T. Sahel J.-A. Sci. Transl. Med. 2010; 2: 26ps16Crossref PubMed Scopus (99) Google Scholar). However, the RdCVF receptor in cones has been unknown, and the mode of action for protecting cones remained unclear. The present study by the Léveillard group (Aït-Ali et al., 2015Aït-Ali N. Fridlich R. Millet-Puel G. Clérin E. Delalande F. Jaillard C. Blond F. Perrocheau L. Reichman S. Byrne L.C. et al.Cell. 2015; 161 (this issue): 817-832Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar) identify an RdCVF receptor, Basigin-1, and propose a mechanism, namely an increase in glucose transport via GLUT1 and a concomitant increase in aerobic glycolysis, that could be responsible for the protection of cones (Figure 1). The authors identify and verify Basigin-1 as the receptor of RdCVF for its trophic function in cones using numerous experimental approaches both in vitro and in vivo. After identifying the receptor, Aït-Ali et al. search for the mechanism leading to enhanced cone survival. Using co-immunoprecipitation followed by mass spectrometry and fluorescence resonance energy transfer assay, they find a glucose transporter, GLUT1, which interacts with Basigin-1. Both Basigin-1 and GLUT1 are expressed in photoreceptor inner segments and are essential for increased cone survival mediated by ectopic RdCVF administration. Aït-Ali et al. point out that cones are highly sensitive to glucose deprivation, suggesting that a glucose uptake-related pathway may underlie the ability of RdCVF to preserve cones. Consistently, using a non-metabolized glucose analog, the authors showed that exposure to RdCVF increased glucose entry into cones. Depletion of Basigin-1 and GLUT1 significantly impairs RdCVF-mediated glucose uptake. How does glucose supply improve cone survival? Aït-Ali et al. observe that cones exposed to RdCVF have increased intracellular ATP concentrations and propose that ATP is produced in an unusual form of aerobic glycolysis, in which glucose is converted to lactate in the presence of oxygen. This metabolic process requires lactate dehydrogenase activity, and its inhibition abolishes RdCVF-mediated cone survival. It has recently been shown that activation of mTORC1 increases cone survival partly by increasing glucose uptake (Venkatesh et al., 2015Venkatesh A. Ma S. Le Y.Z. Hall M.N. Rüegg M.A. Punzo C. J. Clin. Invest. 2015; 125: 1446-1458Crossref PubMed Scopus (98) Google Scholar), suggesting that accelerating glucose entry into the cell is a convergence point for different pathways, such as RdCVF and mTOR, which protect cones. Thus, starvation appears to be a major contributor to cone degeneration in retinitis pigmentosa (Punzo et al., 2009Punzo C. Kornacker K. Cepko C.L. Nat. Neurosci. 2009; 12: 44-52Crossref PubMed Scopus (379) Google Scholar), and feeding cones emerges as a central theme to assist in protecting them. One of the most important implications of the identification of the RdCVF receptor Basigin-1 and its binding partner GLUT1 is the potential for developing small molecules that could activate them and, as a consequence, slow down cone degeneration in patients. One may wonder why researchers are focused on protecting cones, and not on preventing the death of rods? There are a number of reasons. First, since lack of function in rods causes few symptoms, patients often visit ophthalmologists when cones start to be affected. By this time, however, many of the rods have already degenerated. Second, rods should start to be protected before the disease starts. However, the onset of the disease, even if the affected members of a family can be determined early, is often not tractable, complicating the design of clinical trials. Despite these problems, promising new ways of protecting both rods and cones are emerging (Byrne et al., 2015Byrne L.C. Dalkara D. Luna G. Fisher S.K. Clérin E. Sahel J.-A. Léveillard T. Flannery J.G. J. Clin. Invest. 2015; 125: 105-116Crossref PubMed Scopus (107) Google Scholar). In summary, together with exciting new gene therapy approaches to impact oxidative stress (Xiong et al., 2015Xiong W. MacColl Garfinkel A.E. Li Y. Benowitz L.I. Cepko C.L. J. Clin. Invest. 2015; 125: 1433-1445Crossref PubMed Scopus (185) Google Scholar), histone deacetylases (Chen and Cepko, 2009Chen B. Cepko C.L. Science. 2009; 323: 256-259Crossref PubMed Scopus (169) Google Scholar), and RdCVF (Byrne et al., 2015Byrne L.C. Dalkara D. Luna G. Fisher S.K. Clérin E. Sahel J.-A. Léveillard T. Flannery J.G. J. Clin. Invest. 2015; 125: 105-116Crossref PubMed Scopus (107) Google Scholar, Léveillard and Sahel, 2010Léveillard T. Sahel J.-A. Sci. Transl. Med. 2010; 2: 26ps16Crossref PubMed Scopus (99) Google Scholar), small molecules targeting Basigin-1 or GLUT1 may provide ways of slowing down a devastating cause of blindness. Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic GlycolysisAït-Ali et al.CellMay 07, 2015In BriefThe rod-derived cone viability factor RdCVF promotes retinal cone survival by accelerating the entry of glucose into photoreceptors and enhancing aerobic glycolysis. RdCVF acts by binding to the cell-surface complex BSG1/GLUT1, a pathway also used by fast dividing cancer cells. Full-Text PDF Open Archive
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