Yuan Zhe-Feng, Mao Shan-Shan, Shen Jue, Jiang Li-Hua, Xu Lu, Xu Jia-Lu, Gao Feng
Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Front Neurosci. 2020 Jan 29;14:20. doi: 10.3389/fnins.2020.00020. eCollection 2020.
Rett syndrome (RTT) is a neurodevelopmental disease in children that is mainly caused by mutations in the gene, which codes for a transcriptional regulator. The expression of insulin-like growth factor-1 (IGF-1) is reduced in RTT patients and animal models, and IGF-1 treatment is a promising therapeutic strategy for RTT. However, the mechanism underlying the effects of IGF-1 remains to be further explored. FXYD1 is an auxiliary subunit of Na, K-ATPase. Overexpression of FXYD1 is involved in the pathogenesis of RTT. However, whether IGF-1 exerts its effect through normalizing FXYD1 is completely unknown. To this end, we evaluated the effect of IGF-1 on FXYD1 expression and posttranslational modification in a mouse model of RTT (MeCP2) using both and experiments. The results show that FXYD1 mRNA and phosphorylated protein (p-FXYD1) were significantly elevated in the frontal cortex in RTT mice, compared to wild type. In RTT mice, IGF-1 treatment significantly reduced levels of FXYD1 mRNA and p-FXYD1, in parallel with improvements in behavior, motor coordination, and cognitive function. For mechanistic insight into the effect of IGF-1 on p-FXYD1, we found the decreased phosphorylated forms of PI3K-AKT-mTOR signaling pathway components in the frontal cortex of RTT mice and the normalizing effect of IGF-1 on the phosphorylated forms of these components. Interestingly, blocking the PI3K/AKT pathway by PI3K inhibitor could abolish the effect of IGF-1 on p-FXYD1 level, in addition to the effect of IGF-1 on the phosphorylation of other components in the PI3K/AKT pathway. Thus, our study has provided new insights into the mechanism of IGF-1 treatment for RTT, which appears to involve FXYD1.
瑞特综合征（RTT）是一种儿童神经发育疾病，主要由编码转录调节因子的基因突变引起。在RTT患者和动物模型中，胰岛素样生长因子-1（IGF-1）的表达降低，IGF-1治疗是一种有前景的RTT治疗策略。然而，IGF-1作用的潜在机制仍有待进一步探索。FXYD1是钠钾ATP酶的一个辅助亚基。FXYD1的过表达与RTT的发病机制有关。然而，IGF-1是否通过使FXYD1正常化发挥其作用完全未知。为此，我们使用体内和体外实验评估了IGF-1对RTT小鼠模型（MeCP2）中FXYD1表达和翻译后修饰的影响。结果显示，与野生型相比，RTT小鼠额叶皮质中FXYD1 mRNA和磷酸化蛋白（p-FXYD1）显著升高。在RTT小鼠中，IGF-1治疗显著降低了FXYD1 mRNA和p-FXYD1的水平，同时行为、运动协调和认知功能也得到改善。为了深入了解IGF-1对p-FXYD1的作用机制，我们发现RTT小鼠额叶皮质中PI3K-AKT-mTOR信号通路成分的磷酸化形式减少，以及IGF-1对这些成分磷酸化形式的正常化作用。有趣的是，用PI3K抑制剂阻断PI3K/AKT通路除了能消除IGF-1对PI3K/AKT通路中其他成分磷酸化的影响外，还能消除IGF-1对p-FXYD1水平的影响。因此，我们的研究为IGF-1治疗RTT的机制提供了新的见解，这似乎涉及FXYD1。
