Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France.
Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada.
Nat Med. 2018 May;24(5):591-597. doi: 10.1038/s41591-018-0011-0. Epub 2018 May 7.
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.
抑郁症是一种毁灭性的精神疾病,是全球范围内导致残疾的主要原因。目前的抗抑郁药针对该疾病的特定症状,但仍有很大的改进空间。在这方面,针对调节突触可塑性和细胞弹性的信号转导途径的新型化合物,超越了经典的抗抑郁药,具有很高的应用价值。细胞外信号调节激酶 (ERK) 途径与情绪调节有关,但它的多功能性和缺乏靶向特异性限制了最佳药物的开发。在这里,我们确定转录因子 ELK-1(ERK 的下游靶点之一)是抑郁症发病机制和治疗中的一个特定信号模块,可以独立于 ERK 进行靶向治疗。ELK1mRNA 在抑郁症自杀者死后的海马组织中上调;在抑郁症患者的血液样本中,ELK1 表达减少的失败与治疗抵抗有关。在小鼠中,海马 ELK-1 的过表达本身就会产生抑郁行为;相反,选择性抑制 ELK-1 的激活可以防止应激诱导的类似抑郁的分子、可塑性和行为状态。我们的工作强调了基于信号转导的抗抑郁药成功方法的靶向选择性的重要性,将 ELK-1 确定为 ERK 下游与抑郁症相关的转导子,并为 ELK-1 的可药性提供了概念验证证据。