Antidepressive effects of targeting ELK-1 signal transduction

Kallia Apazoglou; Séverine Farley; Victor Gorgievski; Raoul Belzeaux; Juan Pablo Lopez; Julien Grenier; El Chérif Ibrahim; Marie-Anne El Khoury; Yiu C Tse; Raphaele Mongredien; Alexandre Barbé; Carlos E A de Macedo; Wojciech Jaworski; Ariane Bochereau; Alejandro Orrico; Elsa Isingrini; Chloé Guinaudie; Lenka Mikasova; Franck Louis; Sophie Gautron; Laurent Groc; Charbel Massaad; Ferah Yildirim; Vincent Vialou; Sylvie Dumas; Fabio Marti; Naguib Mechawar; Elise Morice; Tak P Wong; Jocelyne Caboche; Gustavo Turecki; Bruno Giros; Eleni T Tzavara

doi:10.1038/s41591-018-0011-0

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Antidepressive effects of targeting ELK-1 signal transduction

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Antidepressive effects of targeting ELK-1 signal transduction

Kallia Apazoglou, Séverine Farley, Victor Gorgievski, Raoul Belzeaux, Juan Pablo Lopez, Julien Grenier, El Chérif Ibrahim, Marie-Anne El Khoury, Yiu C Tse, Raphaele Mongredien, …

Nature medicine, Vol.24(5), pp.591-597

01/05/2018

DOI: https://doi.org/10.1038/s41591-018-0011-0

PMID: 29736027

Résumé

Adult

Animals

Antidepressive Agents - pharmacology

Behavior, Animal

Depression - blood

Depression - genetics

Depression - physiopathology

ets-Domain Protein Elk-1 - blood

ets-Domain Protein Elk-1 - genetics

ets-Domain Protein Elk-1 - metabolism

Female

Hippocampus - metabolism

Humans

Male

Mice

Middle Aged

Neuronal Plasticity

RNA, Messenger - genetics

RNA, Messenger - metabolism

Signal Transduction - drug effects

Stress, Psychological - complications

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted . The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation , but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.

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Titre: Antidepressive effects of targeting ELK-1 signal transduction
Créateurs - sans rôle: Kallia Apazoglou - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Séverine Farley - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Victor Gorgievski - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Raoul Belzeaux - FondaMental Foundation, Créteil, France
Juan Pablo Lopez - Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada
Julien Grenier - Université Paris Descartes
El Chérif Ibrahim - Aix-Marseille Université
Marie-Anne El Khoury - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Yiu C Tse - Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada
Raphaele Mongredien - Neurosciences Paris-Seine
Alexandre Barbé - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Carlos E A de Macedo - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Wojciech Jaworski - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Ariane Bochereau - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Alejandro Orrico - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Elsa Isingrini - Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada
Chloé Guinaudie - Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada
Lenka Mikasova - Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Université de Bordeaux, Bordeaux, France
Franck Louis - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Sophie Gautron - Neurosciences Paris-Seine
Laurent Groc - Institut Interdisciplinaire de Neuroscience
Charbel Massaad - INSERM UMR-S 1124 ERL 3649, Université Paris Descartes, Paris, France
Ferah Yildirim - Department of Neuropsychiatry, Department of Psychiatry and Psychotherapy and NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany
Vincent Vialou - Neurosciences Paris-Seine
Sylvie Dumas - Oramacell, Paris, France
Fabio Marti - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Naguib Mechawar - Douglas Mental Health University Institute
Elise Morice - Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France
Tak P Wong - Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada
Jocelyne Caboche - Neurosciences Paris-Seine
Gustavo Turecki - Douglas Mental Health University Institute
Bruno Giros - FondaMental Foundation, Créteil, France. bruno.giros@mcgill.ca
Eleni T Tzavara - FondaMental Foundation, Créteil, France. eleni.tzavara@inserm.fr
Détails de publication: Nature medicine, Vol.24(5), pp.591-597
Identifiants: 99162991309311
Unité académique: Institut de Génomique Fonctionnelle - IGF
Langue: English
Type de ressource: Journal article