title: Thioredoxin rod-derived cone viability factor protects against photooxidative retinal damage.
abstract: Rod-derived cone viability factor (RdCVF) is a trophic factor of the thioredoxins family that promotes the survival of cone photoreceptors. It is encoded by the nucleoredoxin-like gene 1 Nxnl1 which also encodes by alternative splicing a long form of RdCVF (RdCVFL), a thioredoxin enzyme that interacts with TAU. The known role of thioredoxins in the defense mechanism against oxidative damage led us to examine the retinal phenotype of the Nxnl1(-/-) mice exposed to photooxidative stress. Here we found that, in contrast to wild-type mice, the rod photoreceptors of Nxnl1(-/-) mice are more sensitive to light after exposure to 1700 or 2500 lx. The delivery of RdCVF by AAV to mice deficient of Nxnl1(-/-) protects rod photoreceptors from light damage. Interestingly, the RdCVF2L protein, encoded by the paralog gene Nxnl2, is able to reduce TAU phosphorylation, as does RdCVFL, but does not protect the rod from light damage. Our result shows that the Nxnl1 gene, through the thioredoxin RdCVFL, is part of an endogenous defense mechanism against photooxidative stress that is likely of great importance for human vision.
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: G
authors.initials: G
authors.lastname: Elachouri
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: I
authors.initials: I
authors.lastname: Lee-Rivera
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: E
authors.initials: E
authors.lastname: Clérin
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: M
authors.initials: M
authors.lastname: Argentini
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: R
authors.initials: R
authors.lastname: Fridlich
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: F
authors.initials: F
authors.lastname: Blond
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: V
authors.initials: V
authors.lastname: Ferracane
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Université de Strasbourg CNRS, IGBMC UMR7104, 1 rue Laurent Fries, BP10142, F67404 Illkirch.
authors.forename: W
authors.initials: W
authors.lastname: Raffelsberger
authors.affiliation: Departments of Ophthalmology, Molecular Biology and Genetics, Neuroscience, and Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.affiliation: Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bennett
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France.
authors.forename: J-A
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France; Departments of Ophthalmology, Molecular Biology and Genetics, Neuroscience, and Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Zack
authors.affiliation: INSERM, U968, Paris, F-75012, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 968, Institut de la Vision, Paris, F-75012, France; CNRS, UMR_7210, Paris, F-75012, France. Electronic address: thierry.leveillard@inserm.fr.
authors.forename: T
authors.initials: T
authors.lastname: Léveillard
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002470:Cell Survival; D000229:Dependovirus / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D008027:Light / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005136:Eye Proteins; C558298:Mapt protein, mouse; C525119:RdCVF protein, mouse; C525118:RdCVF-2 protein, mouse; D016875:tau Proteins; D013879:Thioredoxins
keywords: Adeno-associated viral vector; Ligth damage; Photoreceptors; RdCVF; Retinitis pigmentosa; TAU