Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress
Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress
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DOI：
10.1523/jneurosci.1645-05.2005
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发表时间：
2005-08-17
影响因子：
5.3
通讯作者：
Wong, PC
中科院分区：
文献类型：
--
作者：
Cai, HB;Lin, X;Wong, PC
肌萎缩性侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种最常见的运动神经元疾病，是由中枢神经系统运动神经元的选择性丧失引起的。ALS 2基因的突变与一种常染色体隐性青少年型ALS（ALS 2）有关。为了研究ALS 2的致病机制，我们产生了ALS 2敲除（ALS 2（-/-））小鼠。虽然ALS 2（-/-）小鼠没有明显的发育异常，但它们在运动协调和运动学习方面表现出年龄依赖性缺陷。此外，ALS 2（-/-）小鼠在旷场和高架十字迷宫任务中表现出更高的焦虑反应。尽管他们未能概括出与20月龄时的运动神经元疾病一致的临床或神经病理学表型，但与野生型对照组相比，ALS 2（-/-）小鼠或源自这些小鼠的原代培养神经元对氧化应激更敏感。这些观察结果表明，ALS 2功能的丧失不足以在小鼠模型中引起主要的运动缺陷或运动神经元变性，但使神经元易于氧化应激。
Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused by a selective loss of motor neurons in the CNS. Mutations in the ALS2 gene have been linked to one form of autosomal recessive juvenile onset ALS ( ALS2). To investigate the pathogenic mechanisms of ALS2, we generated ALS2 knock-out (ALS2(-/-)) mice. Although ALS2(-/-) mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2(-/-) mice showed a higher anxiety response in the open-field and elevated plus-maze tasks. Although they failed to recapitulate clinical or neuropathological phenotypes consistent with motor neuron disease by 20 months of age, ALS2(-/-) mice or primary cultured neurons derived from these mice were more susceptible to oxidative stress compared with wild-type controls. These observations suggest that loss of ALS2 function is insufficient to cause major motor deficits or motor neuron degeneration in a mouse model but predisposes neurons to oxidative stress.