Glucose to help blindness

11 May 2015 - 10h50 | By INSERM PRESS OFFICE | Neurosciences, cognitives sciences, neurology and psychiatry

The loss of cones, those photoreceptors located in the retina, is the major cause of disability for people with inherited retinal degeneration. Preventing their loss would prevent more than a million people worldwide from becoming blind.

Retinitis pigmentosa, a type of inherited retinal degeneration, is generally diagnosed in young adults. This condition results from progressive degeneration of the photoreceptors located in the retina (rods and cones). Initially, it mainly affects rod function: 1,000 times more sensitive to light than the cones, it is these that contribute to night vision. The most common symptom at the onset of the disease is therefore night blindness. Then, through a chain reaction[1], the cones ultimately degenerate in their turn, and patients suffer from severe sight problems from the age of 40 to 50 years.

Prevention of secondary cone degeneration is therefore a highly promising therapeutic approach. After testing the potential protective effect of 200,000 genes on the eye, Thierry Leveillard and his team demonstrated several years ago that rod-derived cone viability factor (RdCVF) directly induces survival of cones and increases their number. Results of these initial studies showed recovery of sight by patients.

In this new study, published in the journal Cell, Thierry Leveillard and his team have elucidated the mechanism of action of RdCVF on the cones: it promotes their survival by stimulating aerobic glycolysis. Aerobic glycolysis provides the cones with the substrate needed for daily renewal of part of the cone outer segment, the cell structure that carries light-sensitive molecules.

This mechanism involves several intermediaries, including the membrane protein Basigin-1, which is specifically expressed by the photoreceptors. Through the action of RdCVF, it binds to a glucose transporter that promotes the entry of glucose into the cones, which themselves metabolise glucose via aerobic glycolysis.

This highly specific type of glucose metabolism, never described for neuronal cells, is typical of malignant cells, which also proliferate and use large quantities of these metabolites.

“Since we also know that photoreceptors are retinal neurons, our work shows an entirely new neuroprotective mechanism that might affect other neurons,” predicts Thierry Leveillard, Inserm Research Director and author of this work.

“These results also contribute to our work on RdCVF. We identified this factor in 2004, with José Sahel. Its therapeutic action was then proven in animal models in 2009, and more recently in 2015. Tests that should lead to a clinical trial are underway. Understanding how RdCVF acts was indispensable in continuing to write this story of basic research and therapeutic applications.”

[1] It turns out that the rods produce a substance that allows the other category of photoreceptors, the cones, to survive. Without the rods, the cones therefore degenerate.

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Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis

Najate Aı¨t-Ali,1,2,3,13 Ram Fridlich,1,2,3,13 Gé raldine Millet-Puel,1,2,3,13 Emmanuelle Clérin,1,2,3,13 François Delalande,4,5 Céline Jaillard,1,2,3 Frédéric Blond,1,2,3 Ludivine Perrocheau,1,2,3 Sacha Reichman,1,2,3 Leah C. Byrne,6 Anne Olivier-Bandini,7 Jacques Bellalou,8 Emmanuel Moyse,9 Frédéric Bouillaud,10,11,12 Xavier Nicol,1,2,3 Deniz Dalkara,1,2,3 Alain van Dorsselaer,4,5 Jose´ -Alain Sahel,1,2,3 and Thierry Léveillard1,2,3,* 1 Inserm, U968, 75012 Paris, France
2 Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France
3 CNRS, UMR_7210, 75012 Paris, France
4 BioOrganic Mass Spectrometry Laboratory (LSMBO), IPHC, Université de Strasbourg, 25 rue Becquerel, 67087 Strasbourg, France
5 IPHC, CNRS, UMR7178, 67087 Strasbourg, France
6 Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
7 Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France
8 Institut Pasteur, Platform 5 Production of Recombinant Proteins and Antibodies, 75724 Paris Cedex 15, France
9 Unité de Physiologie de la Reproduction et des Comportements (PRC), UMR-85 INRA, Centre INRA de Tours, Université François Rabelais de Tours, 37380 Nouzilly, France
10 Inserm, U1016, Institut Cochin, 75014 Paris, France
11 Cnrs, UMR8104, 75014 Paris, France
12 Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
13 Co-first author


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