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1. Design and validation of the first cell-impermeant melatonin receptor agonist

Author

Gbahou, Florence, Cecon, Erika, Viault, Guillaume, Gerbier, Romain, Jean-Alphonse, Frédéric, Karamitri, Angeliki, Guillaumet, Gérald, Delagrange, Philippe, Friedlander, Robert, Vilardaga, Jean-Pierre, Suzenet, Franck, Jockers, Ralf, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-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), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Unité de Recherches et Découvertes en Neurosciences, Institut de Recherches Servier, University of Pittsburgh (PITT), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Substances d'Origine Naturelle et Analogues Structuraux (SONAS), Université d'Angers (UA), INSERM U691 - Collège de France, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Orléans (UO)-Institut de Chimie du CNRS (INC)

Subjects
[SDV]Life Sciences [q-bio], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction
Abstract

International audience; BACKGROUND AND PURPOSEThe paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT1 and MT2 receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools.EXPERIMENTAL APPROACHWe therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy.KEY RESULTSAmong the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MT1 and MT2 receptors. ICOA-13 showed differential activities on melatonin receptors ranging from partial to full agonistic properties for the Gi/cAMP and ERK pathway and beta-arrestin 2 recruitment. Notably, ICOA-13 enabled us to discriminate between Gi/cAMP signalling of the MT1 receptor initiated at the cell surface and neuronal mitochondria.CONCLUSIONS AND IMPLICATIONSWe report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT1 receptors may have an important impact on the development of novel melatonin receptor ligands relevant for neurodegenerative diseases, such as Huntington disease.

Published
2017

2. Design and validation of the first cell‐impermeant melatonin receptor agonist

Author

Gbahou, Florence, Cecon, Erika, Viault, Guillaume, Gerbier, Romain, Jean‐Alphonse, Frederic, Karamitri, Angeliki, Guillaumet, Gérald, Delagrange, Philippe, Friedlander, Robert M, Vilardaga, Jean‐Pierre, Suzenet, Franck, and Jockers, Ralf

Subjects
Cell Membrane Permeability, Indoles, Dose-Response Relationship, Drug, Molecular Structure, Receptors, Melatonin, Carbocyanines, Ligands, Research Papers, Mice, Structure-Activity Relationship, HEK293 Cells, Drug Design, Ethylamines, Animals, Humans, Pyrroles, Cells, Cultured
Abstract

The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MTWe therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy.Among the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MTWe report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT

Published
2017

3. Update on melatonin receptors: IUPHAR Review 20

Author

Jockers, Ralf, Delagrange, Philippe, Dubocovich, Margarita L., Markus, Regina P., Renault, Nicolas, Tosini, Gianluca, Cecon, Erika, and Zlotos, Darius P.

Subjects
endocrine system, Receptors, Melatonin, Animals, Humans, Ligands, hormones, hormone substitutes, and hormone antagonists, IUPHAR Reviews
Abstract

Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 - encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

Published
2016

4. Update on Melatonin Receptors. IUPHAR Review.: Melatonin Receptors

Author

Jockers, Ralf, Delagrange, Philippe, Dubocovich, Margarita, Markus, Regina, Renault, Nicolas, Tosini, Gianluca, Cecon, Erika, Zlotos, Darius Paul, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Servier, Centre de Recherches de Croissy, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY), Institute of Biosciences, University of São Paulo (USP), Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Morehouse School of Medicine, German University in Cairo [New Cairo City] (GUC), Fondation de la Recherche Médicale (Equipe FRMDEQ20130326503), Institut National de la Santé et de la Recherche Médicale (INSERM),Centre National de la Recherche Scientifique (CNRS) and the 'Who am I?' laboratory ofexcellence No.ANR-11-LABX-0071 funded by the French Government through its'Investments for the Future' program operated by The French National Research Agency(ANR) under grant No.ANR-11-IDEX-0005-01 (to R.J.), USPHS Grants MH-42922, MH52685, DA021870, NS 061068 (to MLD), the National Institutes of Health Grants EY022216 and EY020821 and by 5U54NS083932, S21MD000101, G12-RR03034,U54RR026137 (to G.T.), the São Paulo Research Foundation (FAPESP – Thematic Project -2013/13691-1), Brazilian National Council of Research and Innovation (CNPq – 480097) (toRPM)., ANR-11-BSV1-0012,MLT2D,Les récepteurs de la mélatonine dans le développement du diabète de type 2 chez l'homme(2011), ANR-11-META-0003,MELA-BETES(2011), ANR-12-RPIB-0016,MED-HET-REC-2,Développement de médicaments innovants ciblant les hétéromères des récepteurs couples aux protéines G(2012), 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 ), State University of New York at Buffalo ( SUNY Buffalo ), University of São Paulo ( USP ), Lille Inflammation Research International Center ( LIRIC ), 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 ), German university in Cairo, ANR-11-BSV1-0012,MLT2D,Les récepteurs de la mélatonine dans le développement du diabète de type 2 chez l'homme ( 2011 ), ANR-11-META-0003,MELA-BETES ( 2011 ), ANR-12-RPIB-0016,MED-HET-REC-2,Développement de médicaments innovants ciblant les hétéromères des récepteurs couples aux protéines G ( 2012 ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de São Paulo = University of São Paulo (USP), and 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)

Subjects
endocrine system, genetic variants, GPCR oligomerization, depression, free radical scavenger, neuroprotection, neurodegenerative diseases, sleep disorders, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, type 2 diabetes, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, circadian rhythm disorders, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Melatonin receptors are seven transmembrane-spanning proteins belonging to the G protein-coupled receptor super-family. In mammals, two melatonin receptor subtypes exit MT1 and MT2 encoded by the MTNR1A and MTNR1B genes, respectively. The current review provides an update on melatonin receptors by the corresponding sub-committee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor structures will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by its functions in the immune system and the central nervous system. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

Published
2016

5. Update on Melatonin Receptors. IUPHAR Review.: Melatonin Receptors

Author

Jockers, Ralf, Delagrange, Philippe, Dubocovich, Margarita, Markus, Regina, Renault, Nicolas, Tosini, Gianluca, Cecon, Erika, Zlotos, Darius Paul, Bos, Mireille, BLANC - Les récepteurs de la mélatonine dans le développement du diabète de type 2 chez l'homme - - MLT2D2011 - ANR-11-BSV1-0012 - BLANC - VALID, Appel à Projets Transnational sur le syndrome métabolique et les maladies associées - - MELA-BETES2011 - ANR-11-META-0003 - META - VALID, RECHERCHES PARTENARIALES ET INNOVATION BIOMEDICALE - Développement de médicaments innovants ciblant les hétéromères des récepteurs couples aux protéines G - - MED-HET-REC-22012 - ANR-12-RPIB-0016 - RPIB - VALID, 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), Institut de Recherches Servier, Centre de Recherches de Croissy, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY), Institute of Biosciences, Universidade de São Paulo = University of São Paulo (USP), Lille Inflammation Research International Center - U 995 (LIRIC), 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), Morehouse School of Medicine, German University in Cairo [New Cairo City] (GUC), Fondation de la Recherche Médicale (Equipe FRMDEQ20130326503), Institut National de la Santé et de la Recherche Médicale (INSERM),Centre National de la Recherche Scientifique (CNRS) and the 'Who am I?' laboratory ofexcellence No.ANR-11-LABX-0071 funded by the French Government through its'Investments for the Future' program operated by The French National Research Agency(ANR) under grant No.ANR-11-IDEX-0005-01 (to R.J.), USPHS Grants MH-42922, MH52685, DA021870, NS 061068 (to MLD), the National Institutes of Health Grants EY022216 and EY020821 and by 5U54NS083932, S21MD000101, G12-RR03034,U54RR026137 (to G.T.), the São Paulo Research Foundation (FAPESP – Thematic Project -2013/13691-1), Brazilian National Council of Research and Innovation (CNPq – 480097) (toRPM)., ANR-11-BSV1-0012,MLT2D,Les récepteurs de la mélatonine dans le développement du diabète de type 2 chez l'homme(2011), ANR-11-META-0003,MELA-BETES(2011), and ANR-12-RPIB-0016,MED-HET-REC-2,Développement de médicaments innovants ciblant les hétéromères des récepteurs couples aux protéines G(2012)

Subjects
endocrine system, GPCR oligomerization, genetic variants, depression, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, free radical scavenger, sleep disorders, neuroprotection, neurodegenerative diseases, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, type 2 diabetes, circadian rhythm disorders, hormones, hormone substitutes, and hormone antagonists
Abstract

International audience; Melatonin receptors are seven transmembrane-spanning proteins belonging to the G protein-coupled receptor super-family. In mammals, two melatonin receptor subtypes exit MT1 and MT2 encoded by the MTNR1A and MTNR1B genes, respectively. The current review provides an update on melatonin receptors by the corresponding sub-committee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor structures will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by its functions in the immune system and the central nervous system. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

Published
2016

7. Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels

Author

Erika Cecon, Daniela Fernandois, Nicolas Renault, Caio Fernando Ferreira Coelho, Jan Wenzel, Corentin Bedart, Charlotte Izabelle, Sarah Gallet, Sophie Le Poder, Bernard Klonjkowski, Markus Schwaninger, Vincent Prevot, Julie Dam, Ralf Jockers, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), CHU Lille, FHU 1,000 Days for Health [Lille], Université de Lille, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Universität zu Lübeck = University of Lübeck [Lübeck], Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANRS (Grant No ANRS 0167), ERC Synergy WATCH, No. 810331, Deutsche Forschungsgemeinschaft (WE 6456/1–1, INSERM, CNRS, Fondation de la Recherche Médicale (Equipe FRM DEQ20130326503), La Ligue Contre le Cancer N/Ref: RS19/75–127, Association France Alzheimer (grant No. 2042), Fondation de France, ANR-20-COV4-0001,MELATOVID,Mélatonine et médicaments mélatoninergiques pour la prévention et le traitement de COVID-19(2020), ANR-19-CE16-0025,mitoGPCR,Les récepteurs couplés aux protéines G mitochondriaux en neuroprotection(2019), ANR-16-CE18-0013,Tbeta-ORPH,Nouvelles fonctions pour les récepteurs orphelins couplés aux protéines G – formation d'un complexe entre le récepteur TGFß et GPR50(2016), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Cecon, Erika, Mélatonine et médicaments mélatoninergiques pour la prévention et le traitement de COVID-19 - - MELATOVID2020 - ANR-20-COV4-0001 - COVID-19 - VALID, Les récepteurs couplés aux protéines G mitochondriaux en neuroprotection - - mitoGPCR2019 - ANR-19-CE16-0025 - AAPG2019 - VALID, and Nouvelles fonctions pour les récepteurs orphelins couplés aux protéines G – formation d'un complexe entre le récepteur TGFß et GPR50 - - Tbeta-ORPH2016 - ANR-16-CE18-0013 - AAPG2016 - VALID

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Drug repurposing, Mice, Transgenic, Peptidyl-Dipeptidase A, MESH: Brain, Cellular and Molecular Neuroscience, Mice, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: COVID-19, Animals, MESH: SARS-CoV-2, MESH: Endothelial Cells, Molecular Biology, MESH: Melatonin, Melatonin, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Pharmacology, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, SARS-CoV-2, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, COVID-19, Brain, Endothelial Cells, Cell Biology, Brain infection, COVID-19 Drug Treatment, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, Angiotensin-Converting Enzyme 2, Neuro-vasculature
Abstract

International audience; COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms

Published
2022

8. Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

Author

Erika Cecon, Atsuro Oishi, Marine Luka, Delphine Ndiaye-Lobry, Arnaud François, Mathias Lescuyer, Fany Panayi, Julie Dam, Patricia Machado, Ralf Jockers, Cecon, Erika, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut de Recherches Internationales Servier [Suresnes] (IRIS)

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, General Immunology and Microbiology, General Neuroscience, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Biochemistry, Genetics and Molecular Biology, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred as tauopathies, including frontal temporal dementia and Alzheimer’s disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably reporti.molecular proximity of physiological full-length tau at microtubules;ii.changes in tau conformation and self-interaction associated with tau phosphorylation, as well asiii.tau interaction induced by seeds of recombinant tau or from mouse brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms (i.e.full-length or short fragments, wild-type or the disease-associated tau(P301L) variant) further insights in the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors is aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases.

Published
2022

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