Biondi Olivier, Branchu Julien, Ben Salah Amina, Houdebine Léo, Bertin Lise, Chali Farah, Desseille Céline, Weill Laure, Sanchez Gabriel, Lancelin Camille, Aïd Saba, Lopes Philippe, Pariset Claude, Lécolle Sylvie, Côté Jocelyn, Holzenberger Martin, Chanoine Christophe, Massaad Charbel, Charbonnier Frédéric
Université Paris Descartes and INSERM Unité Mixte de Recherche Scientifique 1124, F-75270 Paris Cedex 06, France.
Centre for Neuromuscular Disease and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, and.
J Neurosci. 2015 Aug 26;35(34):12063-79. doi: 10.1523/JNEUROSCI.0608-15.2015.
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the selective loss of spinal motor neurons due to the depletion of the survival of motor neuron (SMN) protein. No therapy is currently available for SMA, which represents the leading genetic cause of death in childhood. In the present study, we report that insulin-like growth factor-1 receptor (Igf-1r) gene expression is enhanced in the spinal cords of SMA-like mice. The reduction of expression, either at the physiological (through physical exercise) or genetic level, resulted in the following: (1) a significant improvement in lifespan and motor behavior, (2) a significant motor neuron protection, and (3) an increase in SMN expression in spinal cord and skeletal muscles through both transcriptional and posttranscriptional mechanisms. Furthermore, we have found that reducing IGF-1R expression is sufficient to restore intracellular signaling pathway activation profile lying downstream of IGF-1R, resulting in both the powerful activation of the neuroprotective AKT/CREB pathway and the inhibition of the ERK and JAK pathways. Therefore, reducing rather than enhancing the IGF-1 pathway could constitute a useful strategy to limit neurodegeneration in SMA.
Recent evidence of IGF-1 axis alteration in spinal muscular atrophy (SMA), a very severe neurodegenerative disease affecting specifically the motor neurons, have triggered a renewed interest in insulin-like growth factor-1 (IGF-1) pathway activation as a potential therapeutic approach for motor neuron diseases. The present study challenges this point of view and brings the alternative hypothesis that reducing rather than enhancing the IGF-1 signaling pathway exerts a neuroprotective effect in SMA. Furthermore, the present data substantiate a newly emerging concept that the modulation of IGF-1 receptor expression is a key event selectively determining the activation level of intracellular pathways that lie downstream of the receptor. This aspect should be considered when designing IGF-1-based treatments for neurodegenerative diseases.
脊髓性肌萎缩症（SMA）是一种神经肌肉疾病，其特征是由于运动神经元存活蛋白（SMN）的消耗导致脊髓运动神经元选择性丧失。目前尚无针对SMA的治疗方法，SMA是儿童期死亡的主要遗传原因。在本研究中，我们报告胰岛素样生长因子-1受体（Igf-1r）基因表达在SMA样小鼠的脊髓中增强。在生理水平（通过体育锻炼）或基因水平降低该表达会导致以下结果：（1）寿命和运动行为显著改善；（2）运动神经元得到显著保护；（3）通过转录和转录后机制，脊髓和骨骼肌中SMN表达增加。此外，我们发现降低IGF-1R表达足以恢复位于IGF-1R下游的细胞内信号通路激活模式，从而导致神经保护AKT/CREB通路的强大激活以及ERK和JAK通路的抑制。因此，降低而非增强IGF-1通路可能是限制SMA神经退行性变的有用策略。
脊髓性肌萎缩症（SMA）是一种非常严重的神经退行性疾病，专门影响运动神经元，最近有证据表明其IGF-1轴发生改变，这引发了人们对胰岛素样生长因子-1（IGF-1）通路激活作为运动神经元疾病潜在治疗方法的新兴趣。本研究对这一观点提出了挑战，并提出了另一种假设，即降低而非增强IGF-1信号通路在SMA中发挥神经保护作用。此外，本数据证实了一个新出现的概念，即IGF-1受体表达的调节是一个关键事件，选择性地决定受体下游细胞内通路的激活水平。在设计基于IGF-1的神经退行性疾病治疗方法时应考虑这一方面。
