Antidepressive effects of targeting ELK-1 signal transduction

• Published in: Nature Medicine Vol. 24; no. 5; pp. 591 - 597
• Main Authors: Apazoglou, Kallia, Farley, Séverine, Gorgievski, Victor, Belzeaux, Raoul, Lopez, Juan Pablo, Grenier, Julien, Ibrahim, El Chérif, El Khoury, Marie-Anne, Tse, Yiu C, Mongredien, Raphaele, Barbé, Alexandre, de Macedo, Carlos E A, Jaworski, Wojciech, Bochereau, Ariane, Orrico, Alejandro, Isingrini, Elsa, Guinaudie, Chloé, Mikasova, Lenka, Louis, Franck, Gautron, Sophie, Groc, Laurent, Massaad, Charbel, Yildirim, Ferah, Vialou, Vincent, Dumas, Sylvie, Marti, Fabio, Mechawar, Naguib, Morice, Elise, Wong, Tak P, Caboche, Jocelyne, Turecki, Gustavo, Giros, Bruno, Tzavara, Eleni T
• Format: Journal Article Magazine Article
• Language: English
• Published: United States Nature Publishing Group 01.05.2018
• Subjects: Adult; Animals; Antidepressants; Antidepressive Agents - pharmacology; Behavior, Animal; Behavioral plasticity; Cellular signal transduction; Depression (Mood disorder); Depression - blood; Depression - genetics; Depression - physiopathology; Development and progression; Drug development; Drug therapy; Elk; ets-Domain Protein Elk-1 - blood; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Extracellular signal-regulated kinase; Extracellular signal-regulated kinases; Female; Health aspects; Hippocampus; Hippocampus - metabolism; Humans; Job stress; Life Sciences; Major depressive disorder; Male; Mental depression; Mental disorders; Messenger RNA; Metabolic pathways; Mice; Middle Aged; Molecular chains; Mood; Neuronal Plasticity; Neurons and Cognition; Pharmacological research; Physiological aspects; Plastic foam; Plasticity; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - drug effects; Stress, Psychological - complications; Suicide; Synaptic plasticity; Transcription factors; Tricyclic antidepressants
• ISSN: 1078-8956; 1546-170X; 1744-7933
• DOI: 10.1038/s41591-018-0011-0

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.