Over-expression of parvalbumin in transgenic mice rescues motoneurons from injury-induced cell death
Over-expression of parvalbumin in transgenic mice rescues motoneurons from injury-induced cell death
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DOI：
10.1016/j.neuroscience.2003.07.013
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发表时间：
2004-01-01
期刊：
影响因子：
3.3
通讯作者：
Greensmith, L
中科院分区：
文献类型：
--
作者：
Dekkers, J;Bayley, P;Greensmith, L
新生大鼠神经损伤后，很大比例的运动神经元死亡，可能是由于对谷氨酸的兴奋毒性作用的易感性增加所致。钙依赖的谷氨酸兴奋性毒性不仅在损伤诱导的运动神经元死亡中发挥重要作用，而且在肌萎缩侧索硬化症(ALS)等疾病的运动神经元变性中也起着重要作用。运动神经元在谷氨酸受体激活后特别容易受到钙离子内流的影响，因为它们缺乏许多钙结合蛋白，如Calbindin-D-28k和小白蛋白。因此，增加运动神经元缓冲细胞内钙离子的能力可能会保护它们免受细胞死亡的影响，并防止通常由于运动神经元丢失而导致的运动功能下降。在这项研究中，我们通过检测新生轴突切断对正常和转基因小鼠运动神经元存活和肌肉力量产生的影响来测试这种可能性。新生转基因小鼠和野生型小鼠的一条后肢坐骨神经被挤压。8周后，通过对支配胫前肌的运动神经元进行逆行标记，评估对运动神经元存活的影响。在野生型小鼠的神经损伤后，只有20.2%(+/-2.2，S.E.M.；n=4)的受损运动神经元长期存活，而在小白蛋白过度表达的小鼠中，这一比例为47.2%(+/-4.4，S.E.M.；n=4)。令人惊讶的是，运动神经元存活率的显著增加并没有反映在肌肉功能的显著改善上，因为损伤后8周，无论是最大抽动和强直力，还是肌肉重量都没有改善。因此，诱导脊髓运动神经元表达小白蛋白可以保护大部分运动神经元免受损伤诱导的细胞死亡，但这不足以恢复肌肉功能。(C)2003年IBRO。爱思唯尔有限公司出版。保留所有权利。
Following nerve injury in neonatal rats, a large proportion of motoneurons die, possibly as a consequence of an increase in vulnerability to the excitotoxic effects of glutamate. Calcium-dependent glutamate excitotoxicity is thought to play a significant role not only in injury-induced motoneuron death, but also in motoneuron degeneration in diseases such as amyotrophic lateral sclerosis (ALS). Motoneurons are particularly vulnerable to calcium influx following glutamate receptor activation, as they lack a number of calcium binding proteins, such as calbindin-D-28k and parvalbumin. Therefore, it is possible that increasing the ability of motoneurons to buffer intracellular calcium may protect them from cell death and prevent the decline in motor function that usually occurs as a consequence of motoneuron loss. In this study we have tested this possibility by examining the effect of neonatal axotomy on motoneuron survival and muscle force production in normal and transgenic mice that over-express parvalbumin in their motoneurons.The sciatic nerve was crushed in one hindlimb of newborn transgenic and wildtype mice. The effect on motoneuron survival was assessed 8 weeks later by retrograde labelling of motoneurons innervating the tibialis anterior muscle. Following nerve injury in wildtype mice, only 20.2% (+/-2.2, S.E.M.; n=4) of injured motoneurons survive long term compared with 47.2% (+/-4.4, S.E.M.; n=4) in parvalbumin over-expressing mice. Surprisingly, this dramatic increase in motoneuron survival was not reflected in a significant improvement in muscle function, since 8 weeks after injury there was no improvement in either maximal twitch and tetanic force, or muscle weights.Thus, inducing spinal motoneurons to express parvalbumin protects a large proportion of motoneurons from injury-induced cell death, but this is not sufficient to restore muscle function. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.