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2. The Emergence of Rod-Cone Cellular Interaction

Author

Najate Aït-Ali and Thierry Léveillard

Subjects
photoreceptors, glycolysis, thioredoxin, basigin, cell-cell communication, evolution, Genetics, QH426-470
Abstract

We studied the origin of rod-derived cone viability factor (RdCVF) during evolution. In mammals, the nucleoredoxin-like 1 gene (NXNL1) produces a truncated thioredoxin-like protein, RdCVF, by intron retention in rod photoreceptors of the retina. This protein prevents the secondary cone degeneration in animal models of rod-cone degeneration. Extracellular RdCVF binds to a complex at the surface of the cones, composed of the basigin-1, a photoreceptor specific alternative splicing product of the basigin gene, and GLUT1, the glucose transporter. RdCVF accelerates glucose uptake allosterically. Glucose is either metabolized by aerobic glycolysis to sustain cone outer segment renewal or by the pentose phosphate pathway to support redox power to the thioredoxin RdCVFL. RdCVF signaling predates the appearance of the eye and evolved through two alternative splicing events. RdCVF signaling is observed first in hydra where it regulates an unknown signaling. A scallop RdCVF protein is produced by ciliated photoreceptors of the retina and binds its receptor, BSG1, the first occurrence of RdCVF/BSG1 signaling. In the lamprey, RdCVF metabolic signaling between rod and cones is fully operational. In the mouse, the production of BSG1 is regulated through alternative splicing. This signaling was extended to other regions of the brain, via its paralogue NXNL2.

Published
2022
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3. 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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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 Emergence of the Metabolic Signaling of the Nucleoredoxin-like Genes during Evolution

Author

Najate Aït-Ali, Frédéric Blond, Emmanuelle Clérin, Ala Morshedian, Quénol Cesar, François Delalande, Mitsumasa Koyanagi, Catherine Birck, John Han, Xiaoyuan Ren, Alain van Dorsselaer, Akihisa Terakita, Gordon L. Fain, and Thierry Léveillard

Subjects
genetic structures, sense organs
Abstract

SUMMARYThe nucleoredoxin-like genes NXNL1 and NXNL2 were identified through the biological activity of rod-derived cone viability factors (RdCVF and RdCVF2), the alternatively spliced variants produced by intron retention, that mediate signaling between rod and cone photoreceptors by stimulating glucose uptake. These therapeutic genes for inherited retinal degenerations also produce by splicing thioredoxin-like proteins that reduce oxidized cysteines in photoreceptor proteins. The first NXNL genes date from the first animal phyla. Intron retention produces an active RdCVF protein in the tentacles of Hydra vulgaris, a species without eyes. A Scallop RdCVF protein is produced by ciliated photoreceptors of the retina and binds its receptor, BSG1. In the lamprey, a descendent of early vertebrates, RdCVF metabolic signaling between rod and cones is fully established. In the mouse, the production of BSG1 by photoreceptors is regulated by cell-specific splicing inhibition. RdCVF signaling predates photoreceptors and evolved through two alternative splicing events.

Published
2022
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6. 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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7. Cell Signaling with Extracellular Thioredoxin and Thioredoxin-Like Proteins: Insight into Their Mechanisms of Action

Author

Thierry Léveillard, Najate Aït-Ali, 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), and HAL UPMC, Gestionnaire

Subjects
0301 basic medicine, Aging, Cell signaling, Article Subject, Thioredoxin reductase, Review Article, Biology, Pentose phosphate pathway, Biochemistry, 03 medical and health sciences, Thioredoxins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Extracellular, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Secretion, lcsh:QH573-671, chemistry.chemical_classification, 030102 biochemistry & molecular biology, lcsh:Cytology, Cell Biology, General Medicine, Cell biology, 030104 developmental biology, Enzyme, chemistry, Thioredoxin, Signal transduction, Signal Transduction
Abstract

Thioredoxins are small thiol-oxidoreductase enzymes that control cellular redox homeostasis. Paradoxically, human thioredoxin (TXN1) was first identified as the adult T cell leukemia-derived factor (ADF), a secreted protein. ADF has been implicated in a wide variety of cell-to-cell communication systems acting as a cytokine or a chemokine. TRX80 is a truncated TXN1 protein with cytokine activity. The unconventional secretion mechanism of these extracellular thioredoxins is unknown. The thioredoxin system is relying on glucose metabolism through the pentose phosphate pathway that provides reducing power in the form of NADPH, the cofactor of thioredoxin reductase (TXNRD). While a complete extracellular TXN system is present in the blood in the form of circulating TXN1 and TXNDR1, the source of extracellular NADPH remains a mystery. In the absence of redox regenerating capacity, extracellular thioredoxins may rather be prooxidant agents. Rod-derived cone viability factor (RdCVF) is the product of intron retention of the nucleoredoxin-like 1 (NXNL1) gene, a secreted truncated thioredoxin-like protein. The other product encoded by the gene, RdCVFL, is an enzymatically active thioredoxin. This is a very singular example of positive feedback of a superthioredoxin system encoded by a single gene likely emerging during evolution from metabolic constraints on redox signaling.

Published
2017
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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. 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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10. Identification of an Alternative Splicing Product of the Otx2 Gene Expressed in the Neural Retina and Retinal Pigmented Epithelial Cells

Author

Géraldine Millet-Puel, Thierry Léveillard, Delphine Pagan, Valérie Fontaine, Patrick Wincker, Olivier Poch, José-Alain Sahel, Christo Kole, Corinne Da Silva, Frédéric Blond, Najate Aït-Ali, Donald J. Zack, Laetitia Poidevin, Raymond Ripp, Naomi Berdugo, HAL UPMC, Gestionnaire, 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), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-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 la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), 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), Johns Hopkins University (JHU), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Retinal dehydrogenase, Swine, Aucun, lcsh:Medicine, Gene Expression, Retinal Pigment Epithelium, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biochemistry, chemistry.chemical_compound, Database and Informatics Methods, Mice, 0302 clinical medicine, Gene expression, Medicine and Health Sciences, Protein Isoforms, lcsh:Science, Promoter Regions, Genetic, Cells, Cultured, Mammals, Multidisciplinary, Otx Transcription Factors, Monophenol Monooxygenase, Agriculture, Chromatin, Enzymes, medicine.anatomical_structure, Vertebrates, Anatomy, Oxidoreductases, Luciferase, Sequence Analysis, Research Article, Livestock, DNA, Complementary, Ocular Anatomy, Molecular Sequence Data, Sequence Databases, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Research and Analysis Methods, Transfection, Retina, 03 medical and health sciences, Ocular System, DNA-binding proteins, medicine, Genetics, Animals, Gene Regulation, Amino Acid Sequence, RNA, Messenger, Molecular Biology Techniques, Sequencing Techniques, Gene, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene Library, [SDV.GEN]Life Sciences [q-bio]/Genetics, Retinal pigment epithelium, cDNA library, lcsh:R, Alternative splicing, Organisms, Biology and Life Sciences, Proteins, Retinal, Molecular biology, Regulatory Proteins, Rats, Mice, Inbred C57BL, Alcohol Oxidoreductases, Alternative Splicing, 030104 developmental biology, Biological Databases, chemistry, Enzymology, lcsh:Q, sense organs, 030217 neurology & neurosurgery, Cloning, Transcription Factors
Abstract

International audience; 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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11. 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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12. 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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13. 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

14. The homeobox gene CHX10/VSX2 regulates RdCVF promoter activity in the inner retina

Author

Sophie Lambard, Sacha Reichman, Raymond Ripp, Najate Aït-Ali, Thierry Léveillard, Ravi Kiran Reddy Kalathur, Yanjiang Yang, Olivier Poch, Donald J. Zack, Aurélie Lardenois, José-Alain Sahel, 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 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), Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, ANR Chaire d'excellence, This work was supported by Inserm, CIFRE, ANR Chaire d'excellence, NIH, and EVI-GENORET., European Project: 29850,EVI-GENORET, 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), Marazova, Katia, and Functional Genomics of the Retina in Health and Disease - EVI-GENORET - 29850 - OLD

Subjects
genetic structures, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Thioredoxins, MESH: Thioredoxins, MESH: Eye Proteins, MESH: Animals, Promoter Regions, Genetic, Genetics (clinical), Regulation of gene expression, Zinc finger, Mice, Knockout, 0303 health sciences, Mice, Inbred BALB C, MESH: Retina, Genes, Homeobox, General Medicine, Transfection, Articles, MESH: Transcription Factors, MESH: Gene Expression Regulation, medicine.anatomical_structure, Retinitis Pigmentosa, Protein Binding, MESH: Mice, Inbred BALB C, Biology, Retina, 03 medical and health sciences, Retinitis pigmentosa, MESH: Homeodomain Proteins, MESH: Promoter Regions, Genetic, Genetics, medicine, Animals, Humans, MESH: Protein Binding, Eye Proteins, Molecular Biology, Transcription factor, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Genes, Homeobox, medicine.disease, Molecular biology, eye diseases, Gene Expression Regulation, Homeobox, PAX4, MESH: Retinitis Pigmentosa, sense organs, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Rod-derived Cone Viability Factor (RdCVF) is a trophic factor with therapeutic potential for the treatment of retinitis pigmentosa, a retinal disease that commonly results in blindness. RdCVF is encoded by Nucleoredoxin-like 1 (Nxnl1), a gene homologous with the family of thioredoxins that participate in the defense against oxidative stress. RdCVF expression is lost after rod degeneration in the first phase of retinitis pigmentosa, and this loss has been implicated in the more clinically significant secondary cone degeneration that often occurs. Here, we describe a study of the Nxnl1 promoter using an approach that combines promoter and transcriptomic analysis. By transfection of selected candidate transcription factors, chosen based upon their expression pattern, we identified the homeodomain proteins CHX10/VSX2, VSX1 and PAX4, as well as the zinc finger protein SP3, as factors that can stimulate both the mouse and human Nxnl1 promoter. In addition, CHX10/VSX2 binds to the Nxnl1 promoter in vivo. Since CHX10/VSX2 is expressed predominantly in the inner retina, this finding motivated us to demonstrate that RdCVF is expressed in the inner as well as the outer retina. Interestingly, the loss of rods in the rd1 mouse, a model of retinitis pigmentosa, is associated with decreased expression of RdCVF by inner retinal cells as well as by rods. Based upon these results, we propose an alternative therapeutic strategy aimed at recapitulating RdCVF expression in the inner retina, where cell loss is not significant, to prevent secondary cone death and central vision loss in patients suffering from retinitis pigmentosa.

Published
2010
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