Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality
Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality
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DOI：
10.1093/hmg/dds540
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发表时间：
2013-04-01
影响因子：
3.5
通讯作者：
Wirth, Brunhilde
中科院分区：
文献类型：
--
作者：
Ackermann, Bastian;Kroeber, Sandra;Wirth, Brunhilde
F-肌动蛋白集束纤维蛋白3（PLS 3）是神经肌肉疾病脊髓性肌萎缩症（SMA）的完全保护性修饰剂，脊髓性肌萎缩症是婴儿死亡的最常见遗传原因。条件性PLS 3过表达小鼠的产生及其在SMA背景中的繁殖使我们能够破译PLS 3介导的SMA保护的确切生物学机制。我们表明，PLS 3是一个关键的调节器，恢复主要过程取决于肌动蛋白动力学在SMA运动神经元（MN）。与SMA小鼠相比，SMA（PLS 3）中MN索马体大小显著增加，并且传入本体感受输入的数量更高。PLS 3增加突触前F-肌动蛋白的量，拯救突触囊泡和活动区的含量，恢复可释放囊泡池的组织化，并增加神经肌肉接头（NMJ）的量子含量。最值得注意的是，PLS 3过表达导致轴突的稳定，这反过来导致轴突修剪的显著延迟，抵消了SMA NMJ处的不良轴突连接。这些发现连同在MN特异性PLS 3过表达后观察到的终板和肌纤维尺寸增加表明PLS 3显著改善神经肌肉传递。事实上，普遍存在的过表达适度改善了SMA小鼠的存活率和运动功能。由于PLS 3似乎独立于Smn发挥作用，因此PLS 3不仅可能是SMA的潜在治疗靶点，而且可能是其他MN疾病的潜在治疗靶点。
F-actin bundling plastin 3 (PLS3) is a fully protective modifier of the neuromuscular disease spinal muscular atrophy (SMA), the most common genetic cause of infant death. The generation of a conditional PLS3-over-expressing mouse and its breeding into an SMA background allowed us to decipher the exact biological mechanism underlying PLS3-mediated SMA protection. We show that PLS3 is a key regulator that restores main processes depending on actin dynamics in SMA motor neurons (MNs). MN soma size significantly increased and a higher number of afferent proprioceptive inputs were counted in SMA(PLS3) compared with SMA mice. PLS3 increased presynaptic F-actin amount, rescued synaptic vesicle and active zones content, restored the organization of readily releasable pool of vesicles and increased the quantal content of the neuromuscular junctions (NMJs). Most remarkably, PLS3 over-expression led to a stabilization of axons which, in turn, resulted in a significant delay of axon pruning, counteracting poor axonal connectivity at SMA NMJs. These findings together with the observation of increased endplate and muscle fiber size upon MN-specific PLS3 over-expression suggest that PLS3 significantly improves neuromuscular transmission. Indeed, ubiquitous over-expression moderately improved survival and motor function in SMA mice. As PLS3 seems to act independently of Smn, PLS3 might be a potential therapeutic target not only in SMA but also in other MN diseases.