Survival motor neuron affects plastin 3 protein levels leading to motor defects.
Survival motor neuron affects plastin 3 protein levels leading to motor defects.
复制标题
生存运动神经元影响塑蛋白3蛋白水平导致运动缺陷。
DOI：
10.1523/jneurosci.5808-11.2012
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发表时间：
2012-04-11
期刊：
影响因子：
--
通讯作者：
Beattie CE
中科院分区：
文献类型：
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作者：
Hao le T;Wolman M;Granato M;Beattie CE
肌动蛋白结合蛋白plastin 3（PLS 3）已被确定为人类运动神经元疾病脊髓性肌萎缩症（SMA）的修饰剂。SMA是由运动神经元存活蛋白（SMN）水平降低引起的，其最严重的形式导致婴儿和幼儿死亡。为了理解PLS 3在SMA中的机制，我们分析了斑马鱼smn突变体中的pls 3 RNA和蛋白。我们发现，在smn−/−突变体中，pls 3蛋白水平严重降低，而pls 3 mRNA水平没有降低。此外，我们表明，当Smn减少时，pls 3 mRNA和蛋白质稳定性均不受影响。这表明SMN影响PLS 3蛋白质产生。我们先前已经表明，在smn突变体中，突触前蛋白SV 2在神经肌肉接头（NMJ）处减少。在运动神经元中转基因驱动人PLS 3挽救了SV 2表达的降低。为了确定PLS 3是否也可以拯救功能，我们对smn突变体进行了行为分析，发现它们在自发游泳和转动方面显著减少。在运动神经元中转基因驱动PLS 3挽救了这两种缺陷。这些数据表明，PLS 3蛋白水平依赖于SMN，并且PLS 3能够挽救由低水平的Smn引起的神经肌肉缺陷和相应的运动表型，这表明降低的PLS 3有助于SMA运动表型。
The actin binding protein plastin 3 (PLS3) has been identified as a modifier of the human motoneuron disease spinal muscular atrophy (SMA). SMA is caused by decreased levels of the survival motor neuron protein (SMN) and in its most severe form causes death in infants and young children. To understand the mechanism of PLS3 in SMA, we have analyzed pls3 RNA and protein in zebrafish smn mutants. We show that Pls3 protein levels are severely decreased in smn−/− mutants without a reduction in pls3 mRNA levels. Moreover, we show that both pls3 mRNA and protein stability are unaffected when Smn is reduced. This indicates that SMN affects PLS3 protein production. We had previously shown that in smn mutants, the presynaptic protein SV2 is decreased at neuromuscular junctions (NMJs). Transgenically driving human PLS3 in motoneurons rescues the decrease in SV2 expression. To determine whether PLS3 could also rescue function, we performed behavioral analysis on smn mutants and found that they had a significant decrease in spontaneous swimming and turning. Driving PLS3 transgenically in motoneurons rescued both of these defects. These data show that PLS3 protein levels are dependent on SMN and that PLS3 is able to rescue the neuromuscular defects and corresponding movement phenotypes caused by low levels of Smn suggesting that decreased PLS3 contributes to SMA motor phenotypes.