Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats
Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats
复制标题
DOI：
10.1172/jci59130
复制
发表时间：
2012-01-01
影响因子：
15.9
通讯作者：
Xia, Xu-Gang
中科院分区：
文献类型：
--
作者：
Huang, Cao;Tong, Jianbin;Xia, Xu-Gang
肌萎缩侧索硬化症（ALS）的特征是进行性运动神经元变性，最终导致瘫痪和死亡。TAR DNA结合蛋白43（TDP-43）的突变与ALS遗传形式的发展有关。现有的TDP-43转基因动物产生有限的运动神经元损失，因此不能忠实地再现ALS的核心表型。在这里，我们报告了多个系列的转基因大鼠，其中ALS相关的突变体人TDP-43的表达仅限于运动神经元或其他类型的神经元和骨骼肌，可以打开和关闭。当转基因启动时，所有这些大鼠都出现了类似ALS的进行性瘫痪。在运动神经元中单独表达突变TDP-43的大鼠比在不同神经元和肌肉细胞中表达疾病基因的大鼠失去了更多的脊髓运动神经元，尽管这些大鼠都出现了显著的骨骼肌去神经萎缩。有趣的是，在转基因表达被关闭后，疾病的进展停止了;在运动神经元有限损失的大鼠中，我们观察到运动功能的急剧恢复，但在运动神经元严重损失的大鼠中，我们只观察到运动功能的中度恢复。我们的发现表明，运动神经元中的突变TDP-43足以促进ALS的发作和进展，并且运动神经元变性是部分可逆的，至少在突变TDP-43转基因大鼠中是如此。
Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. All of these rats developed progressive paralysis reminiscent of ALS when the transgene was switched on. Rats expressing mutant TDP-43 in motor neurons alone lost more spinal motor neurons than rats expressing the disease gene in varying neurons and muscle cells, although these rats all developed remarkable denervation atrophy of skeletal muscles. Intriguingly, progression of the disease was halted after transgene expression was switched off; in rats with limited loss of motor neurons, we observed a dramatic recovery of motor function, but in rats with profound loss of motor neurons, we only observed a moderate recovery of motor function. Our finding suggests that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that motor neuron degeneration is partially reversible, at least in mutant TDP-43 transgenic rats.