IGF-1R Reduction Triggers Neuroprotective Signaling Pathways in Spinal Muscular Atrophy Mice
IGF-1R Reduction Triggers Neuroprotective Signaling Pathways in Spinal Muscular Atrophy Mice
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DOI：
10.1523/jneurosci.0608-15.2015
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发表时间：
2015-08-26
影响因子：
5.3
通讯作者：
Charbonnier, Frederic
中科院分区：
文献类型：
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作者：
Biondi, Olivier;Branchu, Julien;Charbonnier, Frederic
脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种神经肌肉疾病，其特征在于由于运动神经元存活蛋白（survival of motor neuron，SMN）的耗尽而导致脊髓运动神经元的选择性丧失。SMA是儿童死亡的主要遗传原因，目前尚无治疗方法。在本研究中，我们报告，胰岛素样生长因子-1受体（Igf-1 r）基因表达增强SMA样小鼠脊髓。在生理（通过体育锻炼）或遗传水平上的表达减少导致以下结果：（1）寿命和运动行为的显著改善，（2）显著的运动神经元保护，以及（3）通过转录和转录后机制增加脊髓和骨骼肌中的SMN表达。此外，我们已经发现，降低IGF-1 R表达足以恢复位于IGF-1 R下游的细胞内信号传导途径激活谱，导致神经保护性AKT/CREB途径的强烈激活和ERK和JAK途径的抑制。因此，减少而不是增强IGF-1通路可能是限制SMA神经变性的有用策略。
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.