Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy
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DOI：
10.1038/s41598-017-07603-z
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发表时间：
2017-08-15
影响因子：
4.6
通讯作者：
Gangwani, Laxman
中科院分区：
文献类型：
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作者：
Genabai, Naresh K.;Kannan, Annapoorna;Gangwani, Laxman
脊髓性肌萎缩症（SMA）是由存活运动神经元（SMN）蛋白水平低下引起的，以运动神经元变性和肌肉萎缩为特征。呼吸衰竭导致SMA患者死亡，但其潜在的分子机制尚不清楚。锌指蛋白ZPR1与SMN相互作用。ZPR1在SMA患者中下调。我们报道ZPR1在SMN下游发挥作用，调节控制呼吸的膈运动神经元中的HoxA5水平。运动神经元Zpr1基因时空失活下调HoxA5，导致膈运动神经元功能缺陷，导致小鼠呼吸衰竭和围产期死亡。ZPR1水平的调节与HoxA5转录水平直接相关并影响其转录水平。在SMA小鼠中，smn缺乏导致ZPR1和HoxA5下调，导致膈运动神经元变性。ZPR1和HoxA5作为潜在靶点的鉴定为SMA呼吸窘迫治疗策略的制定提供了范例。
Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice. Modulation in ZPR1 levels directly correlates and influences levels of HoxA5 transcription. In SMA mice, SMN-deficiency causes down-regulation of ZPR1 and HoxA5 that result in degeneration of phrenic motor neurons. Identification of ZPR1 and HoxA5 as potential targets provides a paradigm for developing strategies to treat respiratory distress in SMA.