title: Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis.
abstract: Rod-derived cone viability factor (RdCVF) is an inactive thioredoxin secreted by rod photoreceptors that protects cones from degeneration. Because the secondary loss of cones in retinitis pigmentosa (RP) leads to blindness, the administration of RdCVF is a promising therapy for this untreatable neurodegenerative disease. Here, we investigated the mechanism underlying the protective role of RdCVF in RP. We show that RdCVF acts through binding to Basigin-1 (BSG1), a transmembrane protein expressed specifically by photoreceptors. BSG1 binds to the glucose transporter GLUT1, resulting in increased glucose entry into cones. Increased glucose promotes cone survival by stimulation of aerobic glycolysis. Moreover, a missense mutation of RdCVF results in its inability to bind to BSG1, stimulate glucose uptake, and prevent secondary cone death in a model of RP. Our data uncover an entirely novel mechanism of neuroprotection through the stimulation of glucose metabolism.
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Najate
authors.initials: N
authors.lastname: Aït-Ali
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Ram
authors.initials: R
authors.lastname: Fridlich
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Millet-Puel
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clérin
authors.affiliation: BioOrganic Mass Spectrometry Laboratory (LSMBO), IPHC, Université de Strasbourg, 25 rue Becquerel, 67087 Strasbourg, France; IPHC, CNRS, UMR7178, 67087 Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Delalande
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Jaillard
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blond
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Perrocheau
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Sacha
authors.initials: S
authors.lastname: Reichman
authors.affiliation: Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Byrne
authors.affiliation: Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Olivier-Bandini
authors.affiliation: Institut Pasteur, Platform 5 Production of Recombinant Proteins and Antibodies, 75724 Paris Cedex 15, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bellalou
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moyse
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France; Cnrs, UMR8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Nicol
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: Deniz
authors.initials: D
authors.lastname: Dalkara
authors.affiliation: BioOrganic Mass Spectrometry Laboratory (LSMBO), IPHC, Université de Strasbourg, 25 rue Becquerel, 67087 Strasbourg, France; IPHC, CNRS, UMR7178, 67087 Strasbourg, France.
authors.forename: Alain
authors.initials: A
authors.lastname: van Dorsselaer
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: INSERM, U968, 75012 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France; CNRS, UMR_7210, 75012 Paris, France. Electronic address: thierry.leveillard@inserm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Léveillard
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D012160:Retina / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497886:BSG protein, human; D005136:Eye Proteins; D051272:Glucose Transporter Type 1; C488098:NXNL1 protein, human; C525119:RdCVF protein, mouse; C495677:SLC2A1 protein, human; D051926:Basigin; D013879:Thioredoxins; D000469:Alkaline Phosphatase; D005947:Glucose