Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death
Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death
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DOI：
10.1073/pnas.0805422105
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发表时间：
2008-08-26
影响因子：
11.1
通讯作者：
Cleveland, Don W.
中科院分区：
文献类型：
--
作者：
Ilieva, Hristelina S.;Yamanaka, Koji;Cleveland, Don W.
据报道，细胞质动力蛋白（Loa或Cra）的显性突变引起选择性的、年龄依赖性的运动神经元杀伤，而在一种遗传性ALS小鼠模型中，矛盾的是，它减缓了运动神经元的退化和死亡。对Loa动物的检查显示，大直径α -运动神经元的退化没有超过年龄依赖性丧失（仅在18个月后开始），这在Loa和野生型幼崽中是可比的。与loa介导的α -运动神经元缺失形成对比的是，剧烈的、持续的、突变的动力蛋白介导的出生后腰椎本体感觉轴突缺失，伴随着运动神经元兴奋性谷氨酸能输入减少。在由超氧化物歧化酶（SOD1）突变引起的遗传性ALS小鼠模型中，突变的动力蛋白在运动神经元损失最广泛的一种小鼠模型（SODG93A）中适度延长了生存时间，而在终末期运动神经元存活数量较多的模型中，表现出边际（SODG85R）或无（SODG37R）获益。这些发现支持了本体感觉神经元的非细胞自主兴奋毒性作用，适度地加速了遗传性ALS的发病。
Dominant mutations in cytoplasmic dynein (Loa or Cra) have been reported to provoke selective, age-dependent killing of motor neurons, while paradoxically slowing degeneration and death of motor neurons in one mouse model of an inherited form of ALS. Examination of Loa animals reveals no degeneration of large caliber alpha-motor neurons beyond an age-dependent loss (initiating only after 18 months) that was comparable in Loa and wild-type littermates. Absence of Loa-mediated alpha-motor neuron loss contrasted with dramatic, sustained, mutant dynein-mediated postnatal loss of lumbar proprioceptive sensory axons, accompanied by decreased excitatory glutamatergic inputs to motor neurons. In mouse models of inherited ALS caused by mutations in superoxide dismutase (SOD1), mutant dynein modestly prolonged survival in the one mouse model with the most extensive motor neuron loss (SODG93A) while showing marginal (SODG85R) or no (SODG37R) benefit in models with higher numbers of surviving motor neurons at end stage. These findings support a noncell autonomous, excitotoxic contribution from proprioceptive sensory neurons that modestly accelerates disease onset in inherited ALS.