Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF
Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF
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DOI：
10.1038/nn1653
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发表时间：
2006-03-01
影响因子：
25
通讯作者：
Caroni, P
中科院分区：
文献类型：
--
作者：
Pun, S;Santos, AF;Caroni, P
神经退行性疾病可能具有较长的临床前阶段和潜伏的进展模式，但对疾病进展的机制知之甚少。由于缺乏对受疾病影响的神经元回路的定量描述，因此仍然不清楚疾病进展是否反映了不同突触或轴突的随机损失或时间定义的选择性脆弱性的过程。在这里，我们推导出一个定量地形图的肌肉神经支配的后肢。我们发现，在两个小鼠模型的运动神经元疾病（G93 A SOD 1和G85 R SOD 1），轴突的快速疲劳运动神经元受到影响的同步，很久之前出现症状。抗快疲劳的运动神经元轴突在疲劳发作时受到影响，而慢运动神经元的轴突则具有抵抗性。轴突脆弱性导致突触囊泡停滞和BC 12 a1-a（一种抗凋亡蛋白）的积累。睫状神经营养因子可缓解该症状，并触发外周轴突分支的蛋白酶体依赖性修剪。因此，运动神经元疾病涉及可预测的，选择性的脆弱性模式的生理亚型的轴突，事件的突然修剪在目标区域和补偿的抗性轴突。
Neurodegenerative diseases can have long preclinical phases and insidious progression patterns, but the mechanisms of disease progression are poorly understood. Because quantitative accounts of neuronal circuitry affected by disease have been lacking, it has remained unclear whether disease progression reflects processes of stochastic loss or temporally defined selective vulnerabilities of distinct synapses or axons. Here we derive a quantitative topographic map of muscle innervation in the hindlimb. We show that in two mouse models of motoneuron disease (G93A SOD1 and G85R SOD1), axons of fast-fatiguable motoneurons are affected synchronously, long before symptoms appear. Fast-fatigue-resistant motoneuron axons are affected at symptom-onset, whereas axons of slow motoneurons are resistant. Axonal vulnerability leads to synaptic vesicle stalling and accumulation of BC12a1-a, an anti-apoptotic protein. It is alleviated by ciliary neurotrophic factor and triggers proteasome-dependent pruning of peripheral axon branches. Thus, motoneuron disease involves predictable, selective vulnerability patterns by physiological subtypes of axons, episodes of abrupt pruning in the target region and compensation by resistant axons.