Center of Emphasis in Neurosciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
Sci Rep. 2017 Aug 15;7(1):8295. doi: 10.1038/s41598-017-07603-z.
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.
脊髓性肌萎缩症（SMA）是由运动神经元存活（SMN）蛋白水平降低引起的，其特征是运动神经元退化和肌肉萎缩。呼吸衰竭导致 SMA 患者死亡，但潜在的分子机制尚不清楚。锌指蛋白 ZPR1 与 SMN 相互作用。SMA 患者中 ZPR1 下调。我们报告 ZPR1 作为 SMN 的下游因子，在呼吸控制的膈神经运动神经元中调节 HoxA5 水平。运动神经元中 Zpr1 基因的时空失活下调 HoxA5 并导致膈神经运动神经元功能缺陷，导致呼吸衰竭和小鼠围产期致死。ZPR1 水平的调节与 HoxA5 转录水平直接相关并产生影响。在 SMA 小鼠中，SMN 缺乏导致 ZPR1 和 HoxA5 的下调，导致膈神经运动神经元退化。鉴定 ZPR1 和 HoxA5 作为潜在靶点为开发治疗 SMA 呼吸窘迫的策略提供了范例。
