Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway
Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway
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DOI：
10.1172/jci46276
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
MacKenzie, Alex
中科院分区：
文献类型：
--
作者：
Farooq, Faraz;Abadia Molina, Francisco;MacKenzie, Alex
脊髓性肌萎缩症（SMA）是一种常染色体隐性遗传的神经退行性疾病，其特征是运动神经元丢失，导致进行性肌肉萎缩。它是由SMN1基因突变或缺失导致的功能性运动神经元生存（SMN）蛋白丧失引起的。SMA的潜在治疗策略是上调SMN蛋白水平。在人和小鼠细胞系中激活STAT5的几种药物可增强SMN 2基因的SMN表达，并可至少部分补偿SMN 1功能蛋白产生的损失。在这里，我们已经证明催乳素（PRL）通过激活STAT 5途径增加SMN水平。PRL增加培养的人和小鼠神经元细胞中SMN mRNA和蛋白水平。STAT5特异性siRNA的管理阻断PRL的作用，表明PRL诱导的SMN编码基因的转录上调是由STAT5的激活介导的。此外，对WT小鼠全身给予PRL诱导脑和脊髓中的SMN表达。重要的是，PRL治疗增加了重度SMA小鼠模型的SMN水平，改善了运动功能，并提高了存活率。我们的研究结果证实了早期的工作，表明STAT5通路激活剂作为治疗SMA的潜在治疗化合物，并确定PRL作为一种有前途的药物。
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that is characterized by the loss of motor neurons, resulting in progressive muscle atrophy. It is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. A potential treatment strategy for SMA is to up regulate levels of SMN protein. Several agents that activate STAT5 in human and mouse cell lines enhance SMN expression from the SMN2 gene and can compensate, at least in part, for the loss of production of a functional protein from SMN1. Here, we have shown that prolactin (PRL) increases SMN levels via activation of the STAT5 pathway. PRL increased SMN mRNA and protein levels in cultured human and mouse neuronal cells. Administration of STAT5-specific siRNA blocked the effects of PRL, indicating that the PRL-induced transcriptional upregulation of the SMN-encoding gene was mediated by activation of STAT5. Furthermore, systemic administration of PRL to WT mice induced SMN expression in the brain and spinal cord. Critically, PRL treatment increased SMN levels, improved motor function, and enhanced survival in a mouse model of severe SMA. Our results confirm earlier work suggesting STAT5 pathway activators as potential therapeutic compounds for the treatment of SMA and identify PRL as one such promising agent.