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Journal Articles Nature Medicine Year : 2018

Antidepressive effects of targeting ELK-1 signal transduction

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Kallia Apazoglou
  • Function : Correspondent author
Fabio Marti

Abstract

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.

Dates and versions

inserm-03942179 , version 1 (16-01-2023)

Identifiers

Cite

Kallia Apazoglou, Séverine Farley, Victor Gorgievski, Raoul Belzeaux, Juan Pablo Lopez, et al.. Antidepressive effects of targeting ELK-1 signal transduction. Nature Medicine, 2018, 24 (5), pp.591-597. ⟨10.1038/s41591-018-0011-0⟩. ⟨inserm-03942179⟩
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