Loss of TDP-43 causes age-dependent progressive motor neuron degeneration
Loss of TDP-43 causes age-dependent progressive motor neuron degeneration
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DOI：
10.1093/brain/awt029
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发表时间：
2013-05-01
期刊：
影响因子：
14.5
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Iguchi, Yohei;Katsuno, Masahisa;Sobue, Gen
肌萎缩侧索硬化症是一种破坏性的、进行性的神经退行性疾病，影响上下运动神经元。虽然有几个基因被确定为家族性病例的原因，但占肌萎缩性侧索硬化症90%的散发性形式的发病机制尚未阐明。交互反应DNA结合蛋白43是一种调节RNA加工的核蛋白，在受影响的运动神经元中重新分布到细胞质并形成聚集体，这是散发性肌萎缩侧索硬化症的组织病理学标志，表明交互反应DNA结合蛋白43的功能丧失是神经变性的原因之一。为了验证这一假设，我们使用Cre/loxp系统评估了小鼠出生后运动神经元中反式反应DNA结合蛋白43的敲除效果。这些小鼠在60周龄左右出现进行性体重减轻和运动障碍，并表现出大运动轴突变性、骨骼肌成组萎缩和神经肌肉接头去神经支配。缺乏反式反应DNA结合蛋白43的脊髓运动神经元在1年内没有受到影响，但在100周龄时表现出萎缩;而眼外运动神经元在肌萎缩性侧索硬化症中基本上具有抵抗力，即使在100周龄时也保持不变。此外，超微结构分析显示，自溶酶体和自噬体的细胞体和轴突的运动神经元的100周龄敲除小鼠。总之，在出生后运动神经元中特异性敲除反式反应DNA结合蛋白43的小鼠表现出年龄依赖性进行性运动功能障碍，伴有神经病理学改变，这是散发性肌萎缩侧索硬化症常见的。这些研究结果表明，反式反应DNA结合蛋白43在运动神经元的长期维持中起着至关重要的作用，这种蛋白的功能丧失似乎有助于肌萎缩侧索硬化症的发病机制。
Amyotrophic lateral sclerosis is a devastating, progressive neurodegenerative disease that affects upper and lower motor neurons. Although several genes are identified as the cause of familial cases, the pathogeneses of sporadic forms, which account for 90% of amyotrophic lateral sclerosis, have not been elucidated. Transactive response DNA-binding protein 43 a nuclear protein regulating RNA processing, redistributes to the cytoplasm and forms aggregates, which are the histopathological hallmark of sporadic amyotrophic lateral sclerosis, in affected motor neurons, suggesting that loss-of-function of transactive response DNA-binding protein 43 is one of the causes of the neurodegeneration. To test this hypothesis, we assessed the effects of knockout of transactive response DNA-binding protein 43 in mouse postnatal motor neurons using Cre/loxp system. These mice developed progressive weight loss and motor impairment around the age of 60 weeks, and exhibited degeneration of large motor axon, grouped atrophy of the skeletal muscle, and denervation in the neuromuscular junction. The spinal motor neurons lacking transactive response DNA-binding protein 43 were not affected for 1 year, but exhibited atrophy at the age of 100 weeks; whereas, extraocular motor neurons, that are essentially resistant in amyotrophic lateral sclerosis, remained preserved even at the age of 100 weeks. Additionally, ultra structural analysis revealed autolysosomes and autophagosomes in the cell bodies and axons of motor neurons of the 100-week-old knockout mice. In summary, the mice in which transactive response DNA-binding protein 43 was knocked-out specifically in postnatal motor neurons exhibited an age-dependent progressive motor dysfunction accompanied by neuropathological alterations, which are common to sporadic amyotrophic lateral sclerosis. These findings suggest that transactive response DNA-binding protein 43 plays an essential role in the long term maintenance of motor neurons and that loss-of-function of this protein seems to contribute to the pathogenesis of amyotrophic lateral sclerosis.