Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS
Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS
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DOI：
10.1523/jneurosci.2315-06.2006
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发表时间：
2006-08-23
影响因子：
5.3
通讯作者：
Oppenheim, Ronald W.
中科院分区：
文献类型：
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作者：
Gould, Thomas W.;Buss, Robert R.;Oppenheim, Ronald W.
脑和脊髓运动神经元(MNS)的死亡被认为是肌萎缩侧索硬化症(ALS)发病机制的重要组成部分。我们通过将Bax缺陷小鼠与表达突变超氧化物歧化酶1(SOD1)的小鼠杂交来验证这一假设，SOD1是家族性ALS的转基因模型。虽然Bax缺失未能阻止神经肌肉失神经和线粒体空泡化，但MN完全从突变体SOD1介导的死亡中解救出来。然而，Bax缺乏延长了SOD1突变体的寿命并推迟了运动功能障碍的发生，这表明Bax的作用机制与细胞死亡激活不同。与这一观点一致，Bax的消除推迟了神经肌肉失神经的开始，这种失神经早在SOD1突变体中细胞死亡蛋白激活之前就开始了。此外，我们还发现，去神经支配先于突变型SOD1在MNS内的积累和在脊髓中的星形胶质细胞增生，在Bax缺乏的SOD1突变型中这两者也都被延迟。有趣的是，在神经肌肉失神经开始时，MNS在神经肌肉连接处表现出线粒体异常。此外，在MNS退出轴突之前，MN突触前终末和终末雪旺细胞都表达高水平的突变型SOD1。综上所述，这些数据支持了这样的观点，即ALS的SOD1G93A模型的临床症状是由远端运动轴突损伤而不是死亡途径的激活引起的，并使人对抗细胞凋亡疗法对抗ALS的有效性产生怀疑。此外，他们提出了Bax在促进突变型SOD1介导的运动神经失神经中的一个新的、不依赖于细胞死亡的作用。
The death of cranial and spinal motoneurons (MNs) is believed to be an essential component of the pathogenesis of amyotrophic lateral sclerosis (ALS). We tested this hypothesis by crossing Bax-deficient mice with mice expressing mutant superoxide dismutase 1 (SOD1), a transgenic model of familial ALS. Although Bax deletion failed to prevent neuromuscular denervation and mitochondrial vacuolization, MNs were completely rescued from mutant SOD1-mediated death. However, Bax deficiency extended lifespan and delayed the onset of motor dysfunction of SOD1 mutants, suggesting that Bax acts via a mechanism distinct from cell death activation. Consistent with this idea, Bax elimination delayed the onset of neuromuscular denervation, which began long before the activation of cell death proteins in SOD1 mutants. Additionally, we show that denervation preceded accumulation of mutant SOD1 within MNs and astrogliosis in the spinal cord, which are also both delayed in Bax-deficient SOD1 mutants. Interestingly, MNs exhibited mitochondrial abnormalities at the innervated neuromuscular junction at the onset of neuromuscular denervation. Additionally, both MN presynaptic terminals and terminal Schwann cells expressed high levels of mutant SOD1 before MNs withdrew their axons. Together, these data support the idea that clinical symptoms in the SOD1 G93A model of ALS result specifically from damage to the distal motor axon and not from activation of the death pathway, and cast doubt on the utility of anti-apoptotic therapies to combat ALS. Furthermore, they suggest a novel, cell death-independent role for Bax in facilitating mutant SOD1-mediated motor denervation.