Progressive loss of motor neuron function in wasted mice: Effects of a spontaneous null mutation in the gene for the eEF1A2 translation factor
Progressive loss of motor neuron function in wasted mice: Effects of a spontaneous null mutation in the gene for the eEF1A2 translation factor
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DOI：
10.1093/jnen/64.4.295
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发表时间：
2005-04-01
影响因子：
3.2
通讯作者：
Abbott, CM
中科院分区：
文献类型：
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作者：
Newbery, HJ;Gillingwater, TH;Abbott, CM
Wasted（wst）是一种自发的常染色体隐性突变，其中编码翻译因子cEF 1A 2的基因缺失。纯合子小鼠在断奶后不久表现出震颤和步态障碍，随后运动神经元变性、瘫痪，并在约28天死亡。我们现在已经对这些动物的神经肌肉病理学进行了更详细的分析。出生后19天，在wst/wst颈脊髓中观察到反应性胶质增生，显示吻尾向梯度。几天后，运动神经元空泡化和神经丝积聚，再次出现吻尾向进展。来自17日龄wst/wst小鼠的胸/腹部肌肉显示运动终板的进行性去神经支配的证据，包括弱的突触传递和运动神经末梢的收缩。类似的异常出现在远端，蚓状肌约25日龄。我们的结论是，自发失败的eEF 1A 2表达的浪费突变体首先触发神经胶质细胞在脊髓和肌肉中的运动神经末梢的收缩，然后运动神经元病理和死亡。在wst/wst小鼠中运动单位退化的早期开始和快速进展表明它们应该被认为是人类早发性运动神经元退化的重要和可获得的模型。
Wasted (wst) is a spontaneous autosomal recessive mutation in which the gene encoding translation factor cEF1A2 is deleted. Homozygous mice show tremors and disturbances of gait shortly after weaning, followed by motor neuron degeneration, paralysis, and death by about 28 days. We have now conducted a more detailed analysis of neuromuscular pathology in these animals. Reactive gliosis was observed at 19 days postnatal in wst/wst cervical spinal cord, showing a rostrocaudal gradient. This was followed a few days later by motor neuron vacuolation and neurofilament accumulation, again with a rostrocaudal progression. Tboracic/abdominal muscles from wst/wst mice aged 17 days showed evidence of progressive denervation of motor endplates, including weak synaptic transmission and retraction of motor nerve terminals. Similar abnormalities appeared in distal, lumbrical muscles from about 25 days of age. We conclude that spontaneous failure of eEF1A2 expression in the wasted mutant first triggers gliosis in spinal cord and retraction of motor nerve terminals in muscle, and then motor neuron pathology and death. The early initiation and rapid progression of motor unit degeneration in wst/wst mice suggest that they should be considered an important and accessible model of early-onset motor neuron degeneration in humans.