Antidepressive effects of targeting ELK-1 signal transduction
Kallia Apazoglou
(1)
,
Séverine Farley
(1)
,
Victor Gorgievski
(1)
,
Raoul Belzeaux
(2, 3, 4, 5)
,
Juan Pablo Lopez
(5, 3)
,
Julien Grenier
(6, 7)
,
El Chérif Ibrahim
(4, 8)
,
Marie-Anne El Khoury
(1)
,
Yiu Tse
(3, 5)
,
Raphaele Mongredien
(1)
,
Alexandre Barbé
(1)
,
Carlos de Macedo
(1)
,
Wojciech Jaworski
(1)
,
Ariane Bochereau
(1)
,
Alejandro Orrico
(1)
,
Elsa Isingrini
(5, 3)
,
Chloé Guinaudie
(5, 3)
,
Lenka Mikasova
(9)
,
Franck Louis
(1)
,
Sophie Gautron
(1)
,
Laurent Groc
(9)
,
Charbel Massaad
(6, 7)
,
Ferah Yildirim
(10)
,
Vincent Vialou
(1)
,
Sylvie Dumas
(11)
,
Fabio Marti
(1)
,
Naguib Mechawar
(5, 3)
,
Elise Morice
(1)
,
Tak Wong
(5, 3)
,
Jocelyne Caboche
(1)
,
Gustavo Turecki
(5, 3)
,
Bruno Giros
(1, 5, 3, 4)
,
Eleni Tzavara
(1, 4)
1
NPS -
Neuroscience Paris Seine
2 Hôpitaux Sud - Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM]
3 McGill University = Université McGill [Montréal, Canada]
4 FondaMental Foundation
5 Douglas Mental Health University Institute [Montréal]
6 T3S - UMR_S 1124 - Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire
7 ERL 3649 - Neuroplasticité et thérapie des addictions
8 INT - Institut de Neurosciences de la Timone
9 IINS - Interdisciplinary Institute for Neuroscience [Bordeaux]
10 Charité - UniversitätsMedizin = Berlin University Medicine
11 Oramacell [Paris, France]
2 Hôpitaux Sud - Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM]
3 McGill University = Université McGill [Montréal, Canada]
4 FondaMental Foundation
5 Douglas Mental Health University Institute [Montréal]
6 T3S - UMR_S 1124 - Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire
7 ERL 3649 - Neuroplasticité et thérapie des addictions
8 INT - Institut de Neurosciences de la Timone
9 IINS - Interdisciplinary Institute for Neuroscience [Bordeaux]
10 Charité - UniversitätsMedizin = Berlin University Medicine
11 Oramacell [Paris, France]
Julien Grenier
- Fonction : Auteur
- PersonId : 1395986
- IdHAL : julien-grenier
Elsa Isingrini
- Fonction : Auteur
- PersonId : 749387
- IdHAL : elsa-isingrini
- ORCID : 0000-0002-0698-4237
- IdRef : 152545018
Sophie Gautron
- Fonction : Auteur
- PersonId : 775217
- ORCID : 0000-0002-4510-7640
- IdRef : 09534957X
Fabio Marti
- Fonction : Auteur
- PersonId : 765382
- ORCID : 0000-0002-3604-457X
- IdRef : 131289179
Naguib Mechawar
- Fonction : Auteur
- PersonId : 758310
- ORCID : 0000-0003-4960-756X
Tak Wong
- Fonction : Auteur
- PersonId : 793035
- ORCID : 0000-0001-8611-4911
Jocelyne Caboche
- Fonction : Auteur
- PersonId : 14059
- IdHAL : jocelyne-caboche
- ORCID : 0000-0003-4742-7055
- IdRef : 078678021
Gustavo Turecki
- Fonction : Auteur
- PersonId : 769354
- ORCID : 0000-0003-4075-2736
Bruno Giros
- Fonction : Auteur
- PersonId : 757564
- ORCID : 0000-0001-5876-9822
- IdRef : 032536143
Résumé
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 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, 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 8 , 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.