Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.
Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.
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DOI：
10.1523/jneurosci.0204-12.2012
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发表时间：
2012-06-20
期刊：
影响因子：
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通讯作者：
Sumner CJ
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文献类型：
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作者：
Martinez TL;Kong L;Wang X;Osborne MA;Crowder ME;Van Meerbeke JP;Xu X;Davis C;Wooley J;Goldhamer DJ;Lutz CM;Rich MM;Sumner CJ
遗传性运动神经元疾病脊髓性肌萎缩症 (SMA) 是由运动神经元存活蛋白 (SMN) 表达缺陷引起的，并导致严重的肌肉无力。在 SMA 小鼠中，神经肌肉接头 (NMJ) 和中枢感觉运动突触的突触功能障碍先于运动神经元细胞死亡。为了确定这种突触功能障碍是否是由于运动神经元、肌肉或两者中的 SMN 缺陷所致，我们培育了三系条件性 SMA 小鼠，其 SMN 表达具有组织特异性增加。所有三个品系的小鼠均表现出存活率、体重和运动行为的改善。虽然运动神经元中 SMN 表达的增加可以防止 NMJ 处的突触功能障碍并恢复运动神经元体突触，但肌肉中 SMN 表达的增加并不影响突触功能，尽管它确实改善了肌纤维尺寸。这些数据共同表明，外周和中枢突触完整性都依赖于 SMA 中的运动神经元，但 SMN 在维持这些不同突触方面可能发挥不同的作用。在 NMJ，它以细胞自主的方式在突触前末端发挥作用，但对于运动神经元突触前输入的逆行营养信号传导可能是必需的。重要的是，SMN 似乎也在独立于运动神经元的肌肉生长和/或维持中发挥作用。我们的数据表明，SMN 在肌肉、NMJ 和运动神经元体突触中发挥着不同的作用，并且恢复所有三个部位的 SMN 功能对于肌肉力量的完全恢复是必要的。
The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.