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13 results on '"Géraldine Millet-Puel"'

1. Insulin inhibits inflammation-induced cone death in retinal detachment

Author

Jean-Baptiste Conart, Guillaume Blot, Sébastien Augustin, Géraldine Millet-Puel, Christophe Roubeix, Fanny Beguier, Hugo Charles-Messance, Sara Touhami, José-Alain Sahel, Jean-Paul Berrod, Thierry Léveillard, Xavier Guillonneau, Cécile Delarasse, and Florian Sennlaub

Subjects
Retinal detachment, Cone degeneration, Inflammation, Mononuclear phagocytes, Insulin signaling, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. RD causes the infiltration of activated immune cells, but it is not clear whether and how infiltrating inflammatory cells contribute to cone cell loss. Methods Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD. A mouse model of RD and retinal explants culture were then used to explore the mechanisms leading to cone death. Results Analysis of vitreous samples confirms that RD induces a marked inflammatory response with increased cytokine and chemokine expression in humans, which is closely mimicked by experimental murine RD. In this model, we corroborate that myeloid cells and T-lymphocytes contribute to cone loss, as the inhibition of their accumulation by Thrombospondin 1 (TSP1) increased cone survival. Using monocyte/retinal co-cultures and TSP1 treatment in RD, we demonstrate that immune cell infiltration downregulates rod-derived cone viability factor (RdCVF), which physiologically regulates glucose uptake in cones. Insulin and the insulin sensitizers rosiglitazone and metformin prevent in part the RD-induced cone loss in vivo, despite the persistence of inflammation Conclusion Our results describe a new mechanism by which inflammation induces cone death in RD, likely through cone starvation due to the downregulation of RdCVF that could be reversed by insulin. Therapeutic inhibition of inflammation and stimulation of glucose availability in cones by insulin signaling might prevent RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD. Trial registration ClinicalTrials.gov NCT03318588

Published
2020
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2. The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function

Author

Céline Jaillard, Farah Ouechtati, Emmanuelle Clérin, Géraldine Millet-Puel, Mariangela Corsi, Najate Aït-Ali, Frédéric Blond, Quentin Chevy, Lara Gales, Mélissa Farinelli, Deniz Dalkara, José-Alain Sahel, Jean-Charles Portais, Jean-Christophe Poncer, and Thierry Léveillard

Subjects
Glucose metabolism, Thioredoxin, Tauopathy, Long-term potentiation, Metabolomics, Hippocampus, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

The nucleoredoxin gene NXNL2 encodes for two products through alternative splicing, rod-derived cone viability factor-2 (RdCVF2) that mediates neuronal survival and the thioredoxin-related protein (RdCVF2L), an enzyme that regulates the phosphorylation of TAU. To investigate the link between NXNL2 and tauopathies, we studied the Nxnl2 knockout mouse (Nxnl2−/−). We established the expression pattern of the Nxnl2 gene in the brain using a Nxnl2 reporter mouse line, and characterized the behavior of the Nxnl2−/− mouse at 2 months of age. Additionally, long term potentiation and metabolomic from hippocampal specimens were collected at 2 months of age. We studied TAU oligomerization, phosphorylation and aggregation in Nxnl2−/− brain at 18 months of age. Finally, newborn Nxnl2−/− mice were treated with adeno-associated viral vectors encoding for RdCVF2, RdCVF2L or both and measured the effect of this therapy on long-term potential, glucose metabolism and late-onset tauopathy. Nxnl2−/− mice at 2 months of age showed severe behavioral deficiency in fear, pain sensitivity, coordination, learning and memory. The Nxnl2−/− also showed deficits in long-term potentiation, demonstrating that the Nxnl2 gene is involved in regulating brain functions. Dual delivery of RdCVF2 and RdCVF2L in newborn Nxnl2−/− mice fully correct long-term potentiation through their synergistic action. The expression pattern of the Nxnl2 gene in the brain shows a predominant expression in circumventricular organs, such as the area postrema. Glucose metabolism of the hippocampus of Nxnl2−/− mice at 2 months of age was reduced, and was not corrected by gene therapy. At 18-month-old Nxnl2−/− mice showed brain stigmas of tauopathy, such as oligomerization, phosphorylation and aggregation of TAU. This late-onset tauopathy can be prevented, albeit with modest efficacy, by recombinant AAVs administrated to newborn mice. The Nxnl2−/− mice have memory dysfunction at 2-months that resembles mild-cognitive impairment and at 18-months exhibit tauopathy, resembling to the progression of Alzheimer's disease. We propose the Nxnl2−/− mouse is a model to study multistage aged related neurodegenerative diseases. The NXNL2 metabolic and redox signaling is a new area of therapeutic research in neurodegenerative diseases.

Published
2021
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3. A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells

Author

Laurence Klipfel, Marie Cordonnier, Léa Thiébault, Emmanuelle Clérin, Frédéric Blond, Géraldine Millet-Puel, Saddek Mohand-Saïd, Olivier Goureau, José-Alain Sahel, Emeline F. Nandrot, and Thierry Léveillard

Subjects
retinal pigment epithelium, lactate transport, induced pluripotent stem cells, splicing, MCT3, age-related macular degeneration, Cytology, QH573-671
Abstract

Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.

Published
2021
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4. Identification of an Alternative Splicing Product of the Otx2 Gene Expressed in the Neural Retina and Retinal Pigmented Epithelial Cells.

Author

Christo Kole, Naomi Berdugo, Corinne Da Silva, Najate Aït-Ali, Géraldine Millet-Puel, Delphine Pagan, Frédéric Blond, Laetitia Poidevin, Raymond Ripp, Valérie Fontaine, Patrick Wincker, Donald J Zack, José-Alain Sahel, Olivier Poch, and Thierry Léveillard

Subjects
Medicine, Science
Abstract

To investigate the complexity of alternative splicing in the retina, we sequenced and analyzed a total of 115,706 clones from normalized cDNA libraries from mouse neural retina (66,217) and rat retinal pigmented epithelium (49,489). Based upon clustering the cDNAs and mapping them with their respective genomes, the estimated numbers of genes were 9,134 for the mouse neural retina and 12,050 for the rat retinal pigmented epithelium libraries. This unique collection of retinal of messenger RNAs is maintained and accessible through a web-base server to the whole community of retinal biologists for further functional characterization. The analysis revealed 3,248 and 3,202 alternative splice events for mouse neural retina and rat retinal pigmented epithelium, respectively. We focused on transcription factors involved in vision. Among the six candidates suitable for functional analysis, we selected Otx2S, a novel variant of the Otx2 gene with a deletion within the homeodomain sequence. Otx2S is expressed in both the neural retina and retinal pigmented epithelium, and encodes a protein that is targeted to the nucleus. OTX2S exerts transdominant activity on the tyrosinase promoter when tested in the physiological environment of primary RPE cells. By overexpressing OTX2S in primary RPE cells using an adeno associated viral vector, we identified 10 genes whose expression is positively regulated by OTX2S. We find that OTX2S is able to bind to the chromatin at the promoter of the retinal dehydrogenase 10 (RDH10) gene.

Published
2016
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5. The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function

Author

Emmanuelle Clérin, Frédéric Blond, Mariangela Corsi, Farah Ouechtati, Jean-Charles Portais, Géraldine Millet-Puel, Thierry Léveillard, Mélissa Farinelli, Lara Gales, Deniz Dalkara, Céline Jaillard, Jean Christophe Poncer, José-Alain Sahel, Najate Aït-Ali, Quentin Chevy, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), E-Phy-Science [Biot], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), MetaboHUB-MetaToul, and HAL-SU, Gestionnaire

Subjects
medicine.medical_specialty, Medicine (General), QH301-705.5, Clinical Biochemistry, Hippocampus, Hippocampal formation, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Gene therapy, R5-920, Internal medicine, medicine, Metabolomics, Biology (General), Thioredoxin, 030304 developmental biology, Circumventricular organs, 0303 health sciences, Glucose metabolism, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Organic Chemistry, Alternative splicing, Long-term potentiation, medicine.disease, Tauopathy, Endocrinology, medicine.anatomical_structure, Knockout mouse, Area postrema, Phosphorylation, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Paper
Abstract

International audience; The nucleoredoxin gene NXNL2 encodes for two products through alternative splicing, rod-derived cone viability factor-2 (RdCVF2) that mediates neuronal survival and the thioredoxin-related protein (RdCVF2L), an enzyme that regulates the phosphorylation of TAU. To investigate the link between NXNL2 and tauopathies, we studied the Nxnl2 knockout mouse (Nxnl2−/−). We established the expression pattern of the Nxnl2 gene in the brain using a Nxnl2 reporter mouse line, and characterized the behavior of the Nxnl2−/− mouse at 2 months of age. Additionally, long term potentiation and metabolomic from hippocampal specimens were collected at 2 months of age. We studied TAU oligomerization, phosphorylation and aggregation in Nxnl2−/− brain at 18 months of age. Finally, newborn Nxnl2−/− mice were treated with adeno-associated viral vectors encoding for RdCVF2, RdCVF2L or both and measured the effect of this therapy on long-term potential, glucose metabolism and late-onset tauopathy. Nxnl2−/− mice at 2 months of age showed severe behavioral deficiency in fear, pain sensitivity, coordination, learning and memory. The Nxnl2−/− also showed deficits in long-term potentiation, demonstrating that the Nxnl2 gene is involved in regulating brain functions. Dual delivery of RdCVF2 and RdCVF2L in newborn Nxnl2−/− mice fully correct long-term potentiation through their synergistic action. The expression pattern of the Nxnl2 gene in the brain shows a predominant expression in circumventricular organs, such as the area postrema. Glucose metabolism of the hippocampus of Nxnl2−/− mice at 2 months of age was reduced, and was not corrected by gene therapy. At 18-month-old Nxnl2−/− mice showed brain stigmas of tauopathy, such as oligomerization, phosphorylation and aggregation of TAU. This late-onset tauopathy can be prevented, albeit with modest efficacy, by recombinant AAVs administrated to newborn mice. The Nxnl2−/− mice have memory dysfunction at 2-months that resembles mild-cognitive impairment and at 18-months exhibit tauopathy, resembling to the progression of Alzheimer's disease. We propose the Nxnl2−/− mouse is a model to study multistage aged related neurodegenerative diseases. The NXNL2 metabolic and redox signaling is a new area of therapeutic research in neurodegenerative diseases.

Published
2021
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6. Cone-Enriched Cultures from the Retina of Chicken Embryos to Study Rod to Cone Cellular Interactions

Author

Valérie Fontaine, José-Alain Sahel, Myriam Pinault, Marie Cordonnier, Thierry Léveillard, Géraldine Millet-Puel, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, Hal Sorbonne Université, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Retinal degeneration, genetic structures, [SDV]Life Sciences [q-bio], General Chemical Engineering, Cell Culture Techniques, Chick Embryo, Degeneration (medical), Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, chemistry.chemical_compound, Retinal Rod Photoreceptor Cells, Night vision, Genetic model, Retinitis pigmentosa, medicine, Animals, Mutation, Retina, General Immunology and Microbiology, General Neuroscience, Retinal, medicine.disease, eye diseases, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, chemistry, Retinal Cone Photoreceptor Cells, sense organs, Chickens
Abstract

International audience; Human daytime vision relies on the function of cone photoreceptors at the center of the retina, the fovea. Patients suffering from the most prevalent form of inherited retinal degeneration, retinitis pigmentosa, lose night vision because of mutation driven loss of rod photoreceptors, a phenomenon followed by a progressive loss of function and death of cones leading to blindness. Geneticists have identified many genes with mutations causing this disease, but the first mutations identified questioned the mechanisms of secondary cone degeneration and how a dominant mutation in the rhodopsin gene encoding for the visual pigment expressed exclusively in rods can trigger cone degeneration. This result of transplantations in a genetic model of the disease led to the concept of cell interactions between rods and cones and of non-cell autonomous degeneration of cones in all genetic forms of retinitis pigmentosa. Cones comprise 5% of all photoreceptors in humans and only 3% in the mouse, so their study is difficult in these species, but cones outnumber rods in bird species. We have adapted 96-well plates to culture retinal precursors from the retina of chicken embryos at stage 29 of their development. In these primary cultures, cones represent 80% of the cells after in vitro differentiation. The cells degenerate over a period of one week in the absence of serum. Here, we describe the methods and its standardization. This cone-enriched culture system was used to identify the epithelium-derived cone viability factor (EdCVF) by high content screening of a rat retinal pigmented epithelium normalized cDNA library. Recombinant EdCVF prevents the degeneration of the cones.

Published
2021
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7. A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells

Author

Frédéric Blond, Marie Cordonnier, Saddek Mohand-Said, Thierry Léveillard, Laurence Klipfel, Emmanuelle Clérin, Léa Thiébault, Géraldine Millet-Puel, Emeline F. Nandrot, Olivier Goureau, José-Alain Sahel, HAL-SU, Gestionnaire, Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), and Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Monocarboxylic Acid Transporters, 0301 basic medicine, Lactate transport, induced pluripotent stem cells, retinal pigment epithelium, Biological Transport, Active, MCT3, Biology, lactate transport, Article, Macular Degeneration, 03 medical and health sciences, chemistry.chemical_compound, splicing, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Lactic Acid, Allele, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Induced pluripotent stem cell, Gene, age-related macular degeneration, lcsh:QH301-705.5, Retina, Retinal pigment epithelium, Epithelial Cells, Retinal, General Medicine, Macular degeneration, medicine.disease, eye diseases, 3. Good health, Cell biology, Alternative Splicing, 030104 developmental biology, medicine.anatomical_structure, chemistry, lcsh:Biology (General), [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], sense organs, 030217 neurology & neurosurgery
Abstract

International audience; Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.

Published
2021
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8. Otx2- genetically modified retinal pigment epithelial cells rescue photoreceptors after transplantation

Author

Géraldine Millet-Puel, Emeline F. Nandrot, Frédéric Blond, Olivier Goureau, Thierry Léveillard, Laurence Klipfel, Vanessa Ferracane, Najate Aït-Ali, Ying Yang, Sacha Reichman, Christo Kole, Delphine Pagan, Hawa Camara, José-Alain Sahel, Emmanuelle Clérin, Marie-Noëlle Delyfer, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Rétine, Uvéite et Neuro-Ophtalmologie, CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, Swine, Genetic enhancement, Gene Expression, Retinal Pigment Epithelium, chemistry.chemical_compound, Drug Discovery, neurotrophic factor, induced pluripotent stem-derived cells, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Otx Transcription Factors, Gene therapy of the human retina, Anatomy, gene therapy, 3. Good health, Cell biology, KIR7.1, RCS rats, Molecular Medicine, Original Article, Monocarboxylic Acid Transporters, Epithelial-Mesenchymal Transition, Induced Pluripotent Stem Cells, adeno-associated virus, Biology, Response Elements, 03 medical and health sciences, retinitis pigmentosa, Retinitis pigmentosa, Genetics, medicine, Animals, Humans, Photoreceptor Cells, Potassium Channels, Inwardly Rectifying, age-related macular degeneration, Molecular Biology, Pharmacology, Genetic heterogeneity, Epithelial Cells, Retinal, Macular degeneration, MERTK, medicine.disease, Rats, Transplantation, Alcohol Oxidoreductases, 030104 developmental biology, SLC16A8, chemistry, sense organs, Chickens, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Inherited retinal degenerations are blinding diseases characterized by the loss of photoreceptors. Their extreme genetic heterogeneity complicates treatment by gene therapy. This has motivated broader strategies for transplantation of healthy retinal pigmented epithelium to protect photoreceptors independently of the gene causing the disease. The limited clinical benefit for visual function reported up to now is mainly due to dedifferentiation of the transplanted cells that undergo an epithelial-mesenchymal transition. We have studied this mechanism in vitro and revealed the role of the homeogene OTX2 in preventing dedifferentiation through the regulation of target genes. We have overexpressed OTX2 in retinal pigmented epithelial cells before their transplantation in the eye of a model of retinitis pigmentosa carrying a mutation in Mertk, a gene specifically expressed by retinal pigmented epithelial cells. OTX2 increases significantly the protection of photoreceptors as seen by histological and functional analyses. We observed that the beneficial effect of OTX2 is non-cell autonomous, and it is at least partly mediated by unidentified trophic factors. Transplantation of OTX2-genetically modified cells may be medically effective for other retinal diseases involving the retinal pigmented epithelium as age-related macular degeneration., Graphical Abstract, The homeobox protein OTX2 maintains the differential status of retinal pigmented epithelial (RPE) cells. Transplantation of RPE cells transduced with an adeno-association vector overexpressing OTX2 in the eye of the RCS rat, a model retinitis pigmentosa, ameliorates the protection of vision mediated by rod and cone photoreceptors.

Published
2017
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9. Nxnl2 splicing results in dual functions in neuronal cell survival and maintenance of cell integrity

Author

Aurélie Mouret, Therese Cronin, Thierry Leveillard, José-Alain Sahel, Bernd Kinzel, Marie-Laure Niepon, Olivier Poch, Najate Aït-Ali, Céline Jaillard, Ying Yang, Géraldine Millet-Puel, Alain Trembleau, Wolfgang Raffelsberger, Tina Sedmak, Jean Bennett, Pierre-Marie Lledo, Emmanuelle Clérin, Uwe Wolfrum, Irene Lee-Rivera, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Perception et Mémoire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Johannes Gutenberg - Universität Mainz (JGU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Novartis Pharma AG, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Scheie Eye Institute, University of Pennsylvania [Philadelphia], This work was supported by Inserm, ANR-Neuro 2005 and ANR-MNP 2008 Grants., Marazova, Katia, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), and University of Pennsylvania

Subjects
Sensory Receptor Cells, genetic structures, Cell Survival, RNA Splicing, Sensory system, [SDV.GEN] Life Sciences [q-bio]/Genetics, Olfaction, Biology, Article, Mice, 03 medical and health sciences, Thioredoxins, 0302 clinical medicine, Retinal Rod Photoreceptor Cells, Genetics, Animals, Eye Proteins, Molecular Biology, Gene, Cells, Cultured, Genetics (clinical), 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, General Medicine, Anatomy, Cell biology, RNA splicing, Thioredoxin, 030217 neurology & neurosurgery, Function (biology)
Abstract

International audience; The rod-derived cone viability factors, RdCVF and RdCVF2, have potential therapeutical interests for the treatment of inherited photoreceptor degenerations. In the mouse lacking Nxnl2, the gene encoding RdCVF2, the progressive decline of the visual performance of the cones in parallel with their degeneration, arises due to the loss of trophic support from RdCVF2. In contrary, the progressive loss of rod visual function of the Nxnl2-/- mouse results from a decrease in outer segment length, mediated by a cell autonomous mechanism involving the putative thioredoxin protein RdCVF2L, the second spliced product of the Nxnl2 gene. This novel signaling mechanism extends to olfaction as shown by the progressive impairment of olfaction in aged Nxnl2-/- mice and the protection of olfactory neurons by RdCVF2. This study shows that Nxnl2 is a bi-functional gene involved in the maintenance of both the function and the viability of sensory neurons.

Published
2012
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10. The thioredoxin encoded by the Rod-derived Cone Viability Factor gene protects cone photoreceptors against oxidative stress

Author

Christo Kole, Deniz Dalkara, Jens Duebel, Xin Mei, Najate Aït-Ali, Ying Yang, José-Alain Sahel, Antoine Chaffiol, Emmanuelle Clérin, Jean Bennett, Géraldine Millet-Puel, Thierry Léveillard, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Scheie Eye Institute, University of Pennsylvania [Philadelphia], University of Pennsylvania, and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, genetic structures, Physiology, Cell Survival, Transgene, Clinical Biochemistry, Cre recombinase, [SDV.GEN] Life Sciences [q-bio]/Genetics, Hyperoxia, Biochemistry, Retinal Cone Photoreceptor Cells, Retina, 03 medical and health sciences, Thioredoxins, Retinitis pigmentosa, medicine, Animals, Eye Proteins, Molecular Biology, Gene, Cells, Cultured, General Environmental Science, Mice, Knockout, Mice, Inbred BALB C, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Alternative splicing, Cell Biology, Protective Factors, medicine.disease, Molecular biology, 3. Good health, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, biology.protein, General Earth and Planetary Sciences, GLUT1, sense organs, Thioredoxin, Single-Cell Analysis, Retinitis Pigmentosa
Abstract

International audience; Aims: Rod-derived cone viability factor long (RdCVFL) is an enzymatically active thioredoxin encoded by the nucleoredoxin-like-1 (Nxnl1) gene. The second product of the gene, RdCVF, made by alternative splicing is a novel trophic factor secreted by rods that protects cones in rodent models of retinitis pigmentosa, the most prevalent inherited retinal disease. It acts on the cones by stimulating aerobic glycolysis through its interaction with a complex containing basigin-1 and the glucose transport GLUT1. We studied the role of Nxnl1 in cones after its homologous recombination using a transgenic line expressing Cre recombinase under the control of a cone opsin promoter. Results: We show that the cones of these mice are dysfunctional and degenerate by 8 months of age. The age-related deficit in cones is exacerbated in young animals by exposure to high level of oxygen. In agreement with this phenotype, we found that the cones express only one of the two Nxnl1 gene products, the thioredoxin RdCVFL. Administration of RdCVFL to the mouse carrying a deletion of the Nxnl1 gene in cones reduces the damage produced by oxidative stress. Silencing the expression of RdCVFL in cone-enriched culture reduces cell viability showing that RdCVFL is a cell-autonomous mechanism of protection. Innovation: This novel mode of action is certainly relevant for the therapy of retinitis pigmentosa since the delivery into cones of the rd10 mouse, a recessive model of the disease, rescues cones. Conclusion: Our work highlights the duality of the Nxnl1 gene which protects the cones by two distinct mechanisms.

Published
2016
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11. Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis

Author

Emmanuel Moyse, Emmanuelle Clérin, Géraldine Millet-Puel, Deniz Dalkara, José-Alain Sahel, Najate Aït-Ali, Frédéric Bouillaud, Anne Olivier-Bandini, Thierry Léveillard, Xavier Nicol, Alain Van Dorsselaer, Frédéric Blond, Ram Fridlich, Jacques Bellalou, Leah C. Byrne, François Delalande, Ludivine Perrocheau, Sacha Reichman, Céline Jaillard, Institut de la Vision, Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Helen Wills Neuroscience Institute, University of California [Berkeley], Sanofi Aventis R&D, Production de Protéines Recombinantes (Plate-Forme) ( PRPF ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Physiologie de la reproduction et des comportements [Nouzilly] ( PRC ), Institut National de la Recherche Agronomique ( INRA ) -Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Sanofi, UPMC, Inserm, CNRS, EC, FFB, and ANR, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Production de Protéines Recombinantes (Plate-Forme) (PRPF), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], genetic structures, Glucose uptake, Mutation, Missense, Biology, Retinal Cone Photoreceptor Cells, General Biochemistry, Genetics and Molecular Biology, Retina, Mice, Thioredoxins, Retinitis pigmentosa, medicine, Animals, Humans, [ SDV.OT ] Life Sciences [q-bio]/Other [q-bio.OT], Eye Proteins, Glucose Transporter Type 1, Biochemistry, Genetics and Molecular Biology(all), Glucose transporter, medicine.disease, Alkaline Phosphatase, 3. Good health, Cell biology, Glucose, Biochemistry, Anaerobic glycolysis, biology.protein, Basigin, GLUT1, sense organs, Thioredoxin, Glycolysis, Retinitis Pigmentosa
Abstract

SummaryRod-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.

Published
2015
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12. Therapeutic strategy for handling inherited retinal degenerations in a gene-independent manner using rod-derived cone viability factors

Author

José-Alain Sahel, Najate Aït-Ali, Ying Yang, Emmanuelle Clérin, Ram Fridlich, Céline Jaillard, Géraldine Millet-Puel, Thierry Léveillard, Donald J. Zack, and Alain Van-Dorsselaer

Subjects
Retinal degeneration, genetic structures, Degeneration (medical), Biology, General Biochemistry, Genetics and Molecular Biology, chemistry.chemical_compound, Thioredoxins, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, medicine, Humans, Gene, General Immunology and Microbiology, Retinal Degeneration, Retinal, General Medicine, Cone (category theory), Anatomy, Genetic Therapy, medicine.disease, Cell biology, chemistry, RNA splicing, Retinal Cone Photoreceptor Cells, sense organs, Thioredoxin, General Agricultural and Biological Sciences, Retinitis Pigmentosa
Abstract

The most common hereditary retinal degeneration, retinitis pigmentosa (RP), leads to blindness by degeneration of cone photoreceptors. Meanwhile, genetic studies have shown that a significant proportion of RP genes is expressed only by rods, which raises the question of the mechanism leading to the degeneration of cones. Following the concept of sustainability factor cones, rods secrete survival factors that are necessary to maintain the cones, named Rod-derived Cone Viability Factors (RdCVFs). In patients suffering from RP, loss of rods results in the loss of RdCVFs expression and followed by cone degeneration. We have identified the bifunctional genes nucleoredoxin-like 1 and 2 that encode for, by differential splicing, a thioredoxin enzyme and a cone survival factor, respectively RdCVF and RdCVF2. The administration of these survival factors would maintain cones and central vision in most patients suffering from RP.

Published
2013

13. The thioredoxin-like protein rod-derived cone viability factor (RdCVFL) interacts with TAU and inhibits its phosphorylation in the retina

Author

François Delalande, Olivier Poch, Therese Cronin, Géraldine Millet-Puel, Ram Fridlich, Alain Van Dorsselaer, Arne Holmgren, Céline Jaillard, Jun Lu, Ludivine Perrocheau, Thierry Léveillard, José-Alain Sahel, Marie-Laure Niepon, Laetitia Poidevin, Laboratoire de Physiopathologie Cellulaire et Moleculaire de la Retine, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Biochemistry and Biophysics, karolinska institute-Medical Nobel Institute for Biochemistry, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Peney, Maité, and Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Retinal degeneration, MESH: Protein Isoforms, Biochemistry, MESH: Mice, Knockout, Analytical Chemistry, Mice, Thioredoxins, 0302 clinical medicine, MESH: Thioredoxins, MESH: Eye Proteins, Tandem Mass Spectrometry, Protein Isoforms, MESH: Animals, Phosphorylation, Mice, Knockout, Mice, Inbred BALB C, 0303 health sciences, MESH: Oxidative Stress, biology, MESH: Retina, 3. Good health, MESH: tau Proteins, Signal transduction, Thioredoxin, Protein Binding, Programmed cell death, Tau protein, MESH: Mice, Inbred BALB C, tau Proteins, Retina, Cell Line, 03 medical and health sciences, Retinitis pigmentosa, medicine, Animals, Humans, MESH: Protein Binding, Eye Proteins, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Phosphorylation, Research, Alternative splicing, MESH: Tandem Mass Spectrometry, medicine.disease, Molecular biology, MESH: Cell Line, Oxidative Stress, biology.protein, sense organs, MESH: Chromatography, Liquid, 030217 neurology & neurosurgery, Chromatography, Liquid
Abstract

International audience; Rod-derived cone viability factor (RdCVF) is produced by the Nxnl1 gene that codes for a second polypeptide, RdCVFL, by alternative splicing. Although the role of RdCVF in promoting cone survival has been described, the implication of RdCVFL, a putative thioredoxin enzyme, in the protection of photoreceptors is presently unknown. Using a proteomics approach we identified 90 proteins interacting with RdCVFL including the microtubule-binding protein TAU. We demonstrate that the level of phosphorylation of TAU is increased in the retina of the Nxnl1(-/-) mice as it is hyperphosphorylated in the brain of patients suffering from Alzheimer disease, presumably in some cases through oxidative stress. Using a cell-based assay, we show that RdCVFL inhibits TAU phosphorylation. In vitro, RdCVFL protects TAU from oxidative damage. Photooxidative stress is implicated in retinal degeneration, particularly in retinitis pigmentosa, where it is considered to be a contributor to secondary cone death. The functional interaction between RdCVFL and TAU described here is the first characterization of the RdCVFL signaling pathway involved in neuronal cell death mediated by oxidative stress.

Published
2009
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