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1. Maternal obesity-induced endoplasmic reticulum stress causes metabolic alterations and abnormal hypothalamic development in the offspring

Author

Soyoung Park, Alice Jang, Sebastien G. Bouret, Bodescot, Myriam, Children’s Hospital Los Angeles [Los Angeles], Equipe 'Development and Plasticity of the Neuroendocrine Brain' - LilNCog, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FHU 1,000 Days for Health [Lille], Université de Lille, This study was supported by the National Institutes of Health Grant DK84142 (to SGB)., Laboratory of Development and Plasticity of the Neuroendocrine Brain [Lille], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine -Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, and Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC))

Subjects
Male, Leptin, Pro-Opiomelanocortin, Physiology, Peptide Hormones, Type 2 diabetes, Endoplasmic Reticulum, Biochemistry, Obesity, Maternal, 0302 clinical medicine, Animal Cells, Pregnancy, Medicine and Health Sciences, Biology (General), 2. Zero hunger, Neurons, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Secretory Pathway, Fatty Acids, digestive, oral, and skin physiology, Animal Models, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Endoplasmic Reticulum Stress, Lipids, 3. Good health, Physiological Parameters, Experimental Organism Systems, Hypothalamus, Cell Processes, Prenatal Exposure Delayed Effects, Body Composition, Female, Melanocortin, Cellular Structures and Organelles, Cellular Types, Research Article, medicine.medical_specialty, Offspring, QH301-705.5, Mouse Models, Research and Analysis Methods, Taurochenodeoxycholic Acid, 03 medical and health sciences, Model Organisms, Downregulation and upregulation, Internal medicine, medicine, Animals, Humans, Obesity, Pancreas, 030304 developmental biology, Nutrition, business.industry, Endoplasmic reticulum, Body Weight, Biology and Life Sciences, Neonates, Cell Biology, medicine.disease, Axons, Hormones, Diet, Mice, Inbred C57BL, Endocrinology, Animals, Newborn, alpha-MSH, Cellular Neuroscience, Unfolded protein response, Animal Studies, business, 030217 neurology & neurosurgery, Developmental Biology, Neuroscience
Abstract

The steady increase in the prevalence of obesity and associated type II diabetes mellitus is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of this metabolic disease. Offspring of obese dams developed glucose intolerance and displayed increased body weight, adiposity, and food intake. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were up-regulated in the hypothalamus of neonates born to obese mothers. Neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reversed leptin resistance in the offspring of obese dams., Maternal obesity predisposes offspring to develop obesity and type 2 diabetes in later life, but the mechanisms are unclear. This study shows that the metabolic and hypothalamic defects associated with maternal obesity involve high levels of endoplasmic reticulum stress during critical periods of growth and development.

Published
2020

2. Single Domain Antibody Fragments as New Tools for the Detection of Neuronal Tau Protein in Cells and in Mice Studies

Author

Clément Danis, Morvane Colin, Isabelle Landrieu, Elian Dupre, Jean-Christophe Rain, François-Xavier Cantrelle, Mégane Homa, Hamida Merzougui, Alexis Arrial, Luc Buée, Xavier Hanoulle, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Hybrigenics [Paris], Hybrigenics, Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, ANR-16-IDEX-0004,ULNE,ULNE(2016), ANR-18-CE44-0016,ToNIC,Caractérisation moléculaire et cellulaire de nanobodies dirigés contre Tau(2018), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, and Landrieu, Isabelle

Subjects
Genetically modified mouse, Physiology, Cognitive Neuroscience, [SDV]Life Sciences [q-bio], Tau protein, Variable domain of the heavy-chain only antibodies, Mice, Transgenic, tau Proteins, Context (language use), Biochemistry, Epitope, Mice, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Immunoglobulin Fragments, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, nuclear magnetic resonance spectroscopy, Neurons, 0303 health sciences, biology, Chemistry, tauopathies, Cell Biology, General Medicine, Single-Domain Antibodies, Alzheimer's disease, In vitro, nanobodies, Cell biology, [SDV] Life Sciences [q-bio], Single-domain antibody, Cell culture, biology.protein, Antibody, 030217 neurology & neurosurgery
Abstract

Tau is a neuronal protein linked to pathologies called tauopathies, including Alzheimer's disease. In Alzheimer's disease, tau aggregates into filaments, leading to the observation of intraneuronal fibrillary tangles. Molecular mechanisms resulting in tau aggregation and in tau pathology spreading through the brain regions are still not fully understood. New tools are thus needed to decipher tau pathways involved in the diseases. In this context, a family of novel single domain antibody fragments, or VHHs, directed against tau were generated and characterized. Among the selected VHHs obtained from screening of a synthetic library, a family of six VHHs shared the same CDR3 recognition loop and recognized the same epitope, located in the C-terminal domain of tau. Affinity parameters characterizing the tau/VHHs interaction were next evaluated using surface plasmon resonance spectroscopy. The equilibrium constants KD were in the micromolar range, but despite conservation of the CDR3 loop sequence, a range of affinities was observed for this VHH family. One of these VHHs, named F8-2, was additionally shown to bind tau upon expression in a neuronal cell line model. Optimization of VHH F8-2 by yeast two-hybrid allowed the generation of an optimized VHH family characterized by lower KD than that of the F8-2 wild-type counterpart, and recognizing the same epitope. The optimized VHHs can also be used as antibodies for detecting tau in transgenic mice brain tissues. These results validate the use of these VHHs for in vitro studies, but also their potential for in-cell expression and assays in mouse models, to explore the mechanisms underlying tau physiopathology.

Published
2019

3. Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model

Author

Kadiombo Bantubungi, Luc Buée, Anne Tailleux, David Blum, Emmanuelle Vallez, Sylvie Raison, Elodie Marciniak, Didier Vieau, Tariq Ahmed, Raphaëlle Caillierez, Steve Lancel, Detlef Balschun, Antoine Leboucher, Aurelie Joly-Amado, Emilie Caron, Sabiha Eddarkaoui, Kevin Carvalho, Bart Staels, Malika Hamdane, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Excellence Laboratory LabEx DISTALZ, Brain & Cognition [Leuven, Belgium] (Faculty of Psychology & Educational Sciences), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Faculty of Psychology & Educational Sciences [Leuven, Belgium], Neurological Disorders Research Center [Doha, Qatar], Hamad Bin Khalifa University (HBKU)-Qatar Biomedical Research Institute (QBRI), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Pharmacology and Physiology [Tampa, FL, USA] (Byrd Alzheimer’s Institute ), University of South Florida [Tampa] (USF), This work was supported by grants from France Alzheimer/ Fondation de France (InsTauBrain project), FHU VasCog research network (Lille, France) and programs d'investissements d'avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease). Our laboratories are also supported by ANR (GRAND, SPREADTAU to LB, ADORATAU & ADORASTrAU to DB), Fondation pour la Recherche Médicale, Vaincre Alzheimer, Fondation Plan Alzheimer as well as Inserm, CNRS, Université Lille, Lille Métropole Communauté Urbaine, Région Hauts-de-France, DN2M. AL and KC hold a doctoral grant from Lille 2 University. EM hold a doctoral grant from CHRU and Région Hauts de France. D. Balschun is supported by Research Foundation - Flanders (FWO)., ANR-11-LABX-0009,DISTALZ,Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime(2011), ANR-14-CE13-0031,SPREADTAU,Transfert différentiel intercellulaire des assemblages de Tau(2014), ANR-12-MALZ-0001,ADORATAU,Récepteurs A2A et Tauopathie(2012), ANR-18-CE16-0008,ADORASTrAU,Contribution des astrocytes aux troubles cognitifs induits par la protéine Tau neuronale dans la maladie d'Alzheimer(2018), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of South Florida (USF), ANR-11-LABX-0009/11-LABX-0009,DISTALZ,Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime(2011), ANR-18-CE16-0008,ADORASTRAU,CONTRIBUTION OF ASTROCYTES TO COGNITIVE DEFICITS INDUCED BY NEURONAL TAU IN ALZHEIMER’S DISEASE(2018), Blum, David, Laboratoires d'excellence - Développement de stratégies innovantes pour une approche transdisciplinaire de la maladie d'Alzheime - - DISTALZ2011 - ANR-11-LABX-0009 - LABX - VALID, Appel à projets générique - Transfert différentiel intercellulaire des assemblages de Tau - - SPREADTAU2014 - ANR-14-CE13-0031 - Appel à projets générique - VALID, Maladie d'Alzheimer et Maladies Apparentées - Récepteurs A2A et Tauopathie - - ADORATAU2012 - ANR-12-MALZ-0001 - MALZ - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Contribution des astrocytes aux troubles cognitifs induits par la protéine Tau neuronale dans la maladie d'Alzheimer - - ADORASTrAU2018 - ANR-18-CE16-0008 - AAPG2018 - VALID, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Neuroendocrinologie et physiopathologie neuronale, Institut National de la Santé et de la Recherche Médicale (INSERM), Impact de l'Environnement Chimique sur la Santé Humain, PRES Université Lille Nord de France, Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Environnement périnatal et croissance, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratory of Biological Psychology, and Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)

Subjects
0301 basic medicine, Genetically modified mouse, medicine.medical_specialty, Transgene, medicine.medical_treatment, Hippocampus, Mice, Transgenic, tau Proteins, Energy homeostasis, Hypoinsulinemia, lcsh:RC321-571, 03 medical and health sciences, Mice, 0302 clinical medicine, Insulin resistance, Internal medicine, medicine, Animals, Insulin, Transgenic mice, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, ComputingMilieux_MISCELLANEOUS, biology, Brain, THY-Tau22, Alzheimer's disease, medicine.disease, Mice, Inbred C57BL, Insulin receptor, 030104 developmental biology, Endocrinology, Metabolism, Neurology, Tauopathies, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Tau, 030217 neurology & neurosurgery
Abstract

International audience; Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aβ oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.

Published
2019

4. Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator

Author

Chatterjee, Snehajyoti, Cassel, Raphaelle, Schneider‐Anthony, Anne, Merienne, Karine, Cosquer, Brigitte, Tzeplaeff, Laura, Halder Sinha, Sarmistha, Kumar, Manoj, Chaturbedy, Piyush, Eswaramoorthy, Muthusamy, Le Gras, Stéphanie, Keime, Céline, Bousiges, Olivier, Dutar, Patrick, Petsophonsakul, Petnoi, Rampon, Claire, Cassel, Jean‐Christophe, Buée, Luc, Blum, David, Kundu, Tapas K, Boutillier, Anne‐Laurence, Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Molecular Biology and Genetics Unit [Bangalore, India] (Transcription and Disease Laboratory), Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)-Indian Institute of Science, Chemistry and Physics of Materials Unit [Bangalore, India], Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), 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), Université de Strasbourg (UNISTRA), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Centre de Recherches sur la Cognition Animale - UMR5169 (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, SC was supported by IFCPAR/CEFIPRA (No. 4803-3). RC was a recipient of a doctoral fellowship from the French government. AS-A was supported by the ANR (ANR-12-MALZ-0002-01). LB and DB are supported by programs d’investissements d’avenir LabEx (excellence laboratory) and the DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), France Alzheimer, FHU VasCog research network (Lille, France), Fondation pour la Recherche Médicale, LECMA/Alzheimer Forschung Initiative, Fondation Plan Alzheimer, Inserm, CNRS, Université Lille 2, Lille Métropole Communauté Urbaine, Région Nord/Pas-de- Calais, FEDER, DN2M, and FUI MEDIALZ. This work was supported by the CNRS, the University of Strasbourg, ANR (ANR-12-MALZ-0002-01 to ALB), France Alzheimer (to ALB), the Department of Biotechnology, the Government of India (Grant/DBT/CSH/GIA/1752 to TKK), the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), and the Indo-French Centre for the Promotion of Advanced Research (IFCPAR/CEFIPRA (No. 4803-3 to TKK and ALB))., Institut de psychiatrie et neurosciences (U894 / UMS 1266), Centre de Recherches sur la Cognition Animale (CRCA), Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-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)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Blum, David, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine

Subjects
Medicine (General), [SDV]Life Sciences [q-bio], Enzyme Activators, Mice, Transgenic, QH426-470, Hippocampus, Epigenesis, Genetic, Histones, [SCCO]Cognitive science, R5-920, Memory, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Animals, p300-CBP Transcription Factors, Pharmacology & Drug Discovery, Transgenes, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Articles, ComputingMilieux_MISCELLANEOUS, acetylation, Inflammation, Neuronal Plasticity, learning, CREB‐binding protein, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Alzheimer's disease, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Mice, Inbred C57BL, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Disease Models, Animal, Tauopathies, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Transcriptome, transcription, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Research Article, Neuroscience
Abstract

International audience; Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers. At the epigenomic level, the hippocampus of tauopathic mice showed a significant decrease in H2B but not H3K27 acetylation levels, both marks co-localizing at TSS and CBP enhancers. Importantly, CSP-TTK21 treatment increased H2B acetylation levels at decreased peaks, CBP enhancers, and TSS, including genes associated with plasticity and neuronal functions, overall providing a 95% rescue of the H2B acetylome in tauopathic mice. This study is the first to provide in vivo proof-of-concept evidence that CBP/p300 HAT activation efficiently reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated with Alzheimer's disease lesions in mice.

Published
2018

5. Galectin-3 is a non-classic RNA binding protein that stabilizes the mucin MUC4 mRNA in the cytoplasm of cancer cells

Author

Coppin, Lucie, Vincent, Audrey, Frénois, Frédéric, Duchêne, Belinda, Lahdaoui, Fatima, Stechly, Laurence, Renaud, Florence, Villenet, Céline, Seuningen, Isabelle Van, Leteurtre, Emmanuelle, Dion, Johann, Grandjean, Cyrille, Poirier, Françoise, Figeac, Martin, Delacour, Delphine, Porchet, Nicole, Pigny, Pascal, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Inserm UMR837 Team 5, Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Lisode, Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Laboratoire d'Ingénierie des Systèmes Mécaniques et des MAtériaux (LISMMA), Université Paris 8 Vincennes-Saint-Denis (UP8)-SUPMECA - Institut supérieur de mécanique de Paris, Laboratoire QUARTZ (QUARTZ ), Université Paris 8 Vincennes-Saint-Denis (UP8)-SUPMECA - Institut supérieur de mécanique de Paris-Ecole Nationale Supérieure de l'Electronique et de ses Applications (ENSEA)-Ecole Internationale des Sciences du Traitement de l'Information (EISTI), University of Bern, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre de biologie pathologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN), Mucines Epitheliales : du Gene a la Fonction, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Gestionnaire HAL, ISAE-Supmeca

Subjects
Mice, Knockout, Cytoplasm, Mucin-4, Galectin 3, Galectins, RNA Stability, [SDV]Life Sciences [q-bio], Epithelial Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Blood Proteins, Article, Mice, Inbred C57BL, Pancreatic Neoplasms, Gene Expression Regulation, Animals, Humans, [NLIN] Nonlinear Sciences [physics], RNA, Messenger, [NLIN]Nonlinear Sciences [physics], [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS
Abstract

Pancreatic cancer cells express high levels of MUC1, MUC4 and MUC16 mRNAs that encode membrane-bound mucins. These mRNAs share unusual features such as a long half-life. However, it remains unknown how mucin mRNA stability is regulated. Galectin-3 (Gal-3) is an endogenous lectin playing important biological functions in epithelial cells. Gal-3 is encoded by LGALS3 which is up-regulated in pancreatic cancer. Despite the absence of a RNA-recognition motif, Gal-3 interacts indirectly with pre-mRNAs in the nucleus and promotes constitutive splicing. However a broader role of Gal-3 in mRNA fate is unexplored. We report herein that Gal-3 increases MUC4 mRNA stability through an intermediate, hnRNP-L which binds to a conserved CA repeat element in the 3′UTR in a Gal-3 dependent manner and also controls Muc4 mRNA levels in epithelial tissues of Gal3−/− mice. Gal-3 interacts with hnRNP-L in the cytoplasm, especially during cell mitosis, but only partly associates with protein markers of P-Bodies or Stress Granules. By RNA-IP plus RNA-seq analysis and imaging, we demonstrate that Gal-3 binds to mature spliced MUC4 mRNA in the perinuclear region, probably in hnRNP-L-containing RNA granules. Our findings highlight a new role for Gal-3 as a non-classic RNA-binding protein that regulates MUC4 mRNA post-transcriptionally.

Published
2017

6. Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Author

Arielle R. Rosenberg, Yves Rouillé, Laurence Cocquerel, Czeslaw Wychowski, Thibaut Vausselin, Adeline Danneels, Ahmed Atef Ahmed Abouzeid Mesalam, Matthieu Lemasson, Sandrine Belouzard, Karin Séron, Muriel Lavie, Jean Dubuisson, Patricia Melnyk, Lucie Fénéant, Lander Foquet, Philip Meuleman, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, This work was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS), the ANR through ERA-NET Infect-ERA program (ANR-13-IFEC-0002-01). Philip Meuleman was supported by Ghent University (Concerted Action Grant 01G01712) and the Belgian Science Policy Office (BELSPO, IUAP P7/47-HEPRO-2). Thibaut Vausselin and Matthieu Lemasson were supported by a fellowship from the ANRS. Sandrine Belouzard was supported by a Marie Curie International Reintegration Grant (PIRG-GA-2009-256300). Ahmed Atef Mesalam is the recipient of a Ph.D. fellowship provided by the Egyptian Government. The 300-MHz NMR facilities were funded by the Région Nord-Pas de Calais (France), the Ministère de la Jeunesse, de l'Education Nationale et de la Recherche (MJENR), and the Fonds Européens de Développement Régional (FEDER)., We thank P.-E. Larchanché for the synthesis of the compounds. We are grateful to Gilles Duverlie and Véronique Descamps for core protein quantification. We thank Laure Saas for technical assistance. We are also grateful to R. Bartenschlager, C. Biot, J. Bukh, F.L. Cosset, P. Halfon, J. McKeating, and T. Wakita for providing essential reagents. The immunofluorescence analyses were performed with the help of the imaging core facility of the BioImaging Center Lille Nord-de-France., ANR-13-IFEC-0002,HCV-ASSEMBLY,Identification of host factors involved in Hepatitis C Virus assembly and characterization of their potential role in vivo(2013), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille

Subjects
Models, Molecular, 0301 basic medicine, Hepacivirus, Hepatitis C virus, Immunology, Drug Evaluation, Preclinical, Mutation, Missense, Mice, SCID, Drug resistance, Pharmacology, medicine.disease_cause, Antiviral Agents, Microbiology, Virus, Mice, 03 medical and health sciences, Viral Envelope Proteins, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Viral entry, Virology, Vaccines and Antiviral Agents, Drug Resistance, Viral, medicine, Animals, Humans, Cells, Cultured, Mutation, Molecular Structure, biology, Hepatitis C, Virus Internalization, biology.organism_classification, Resistance mutation, medicine.disease, Reverse Genetics, 3. Good health, Disease Models, Animal, Treatment Outcome, 030104 developmental biology, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Aminoquinolines, Hepatocytes
Abstract

Aminoquinolines and piperazines, linked or not, have been used successfully to treat malaria, and some molecules of this family also exhibit antiviral properties. Here we tested several derivatives of 4-aminoquinolines and piperazines for their activity against hepatitis C virus (HCV). We screened 11 molecules from three different families of compounds, and we identified anti-HCV activity in cell culture for six of them. Of these, we selected a compound (B5) that is currently ending clinical phase I evaluation for neurodegenerative diseases. In hepatoma cells, B5 inhibited HCV infection in a pangenotypic and dose-dependent manner, and its antiviral activity was confirmed in primary hepatocytes. B5 also inhibited infection by pseudoparticles expressing HCV envelope glycoproteins E1 and E2, and we demonstrated that it affects a postattachment stage of the entry step. Virus with resistance to B5 was selected by sequential passage in the presence of the drug, and reverse genetics experiments indicated that resistance was conferred mainly by a single mutation in the putative fusion peptide of E1 envelope glycoprotein (F291I). Furthermore, analyses of the effects of other closely related compounds on the B5-resistant mutant suggest that B5 shares a mode of action with other 4-aminoquinoline-based molecules. Finally, mice with humanized liver that were treated with B5 showed a delay in the kinetics of the viral infection. In conclusion, B5 is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle. IMPORTANCE In the last 4 years, HCV therapy has been profoundly improved with the approval of direct-acting antivirals in clinical practice. Nevertheless, the high costs of these drugs limit access to therapy in most countries. The present study reports the identification and characterization of a compound (B5) that inhibits HCV propagation in cell culture and is currently ending clinical phase I evaluation for neurodegenerative diseases. This molecule inhibits the HCV life cycle by blocking virus entry. Interestingly, after selection of drug-resistant virus, a resistance mutation in the putative fusion peptide of E1 envelope glycoprotein was identified, indicating that B5 could be used to further investigate the fusion mechanism. Furthermore, mice with humanized liver treated with B5 showed a delay in the kinetics of the viral infection. In conclusion, B5 is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle.

Published
2016

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