Temporal Expression of Mutant TDP-43 Correlates with Early Amyotrophic Lateral Sclerosis Phenotype and Motor Weakness.
Temporal Expression of Mutant TDP-43 Correlates with Early Amyotrophic Lateral Sclerosis Phenotype and Motor Weakness.
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突变 TDP-43 的时间表达与早期肌萎缩侧索硬化症表型和运动无力相关
DOI：
10.2174/1567202615666180109161541
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发表时间：
2018
影响因子：
2.1
通讯作者：
Xiao B
中科院分区：
文献类型：
--
作者：
Chen Q;Zhou J;Huang C;Huang B;Bi F;Zhou H;Xiao B
背景：突变的交互反应dna结合蛋白（TDP-43）与肌萎缩性侧索硬化症（ALS）的遗传形式密切相关。TDP-43转基因大鼠可再现ALS的核心表型，TDP-43的组成性表达可引起出生后死亡。目的：了解突变体TDP-43引起的神经功能缺陷是否依赖于其时间表达。方法：建立在神经元中表达突变体人TDP-43 （M337V替代）的转基因大鼠，用Tet-off系统调控其表达。结果：TDP-43突变体转基因大鼠在转基因激活后出现明显虚弱。突变体TDP-43在30天表达的大鼠表现出更强的侵袭性表型。神经源性萎缩病理改变更为严重。结论：大鼠神经元中TDP-43突变体的时间表达促进了严重的表型。TDP-43的功能障碍对运动神经元和骨骼肌的发育有深远的影响。
Background: Mutant transactive response DNA-binding protein (TDP-43) is closely correlated to the inherited form of amyotrophic lateral sclerosis (ALS). TDP-43 transgenic rats can reproduce the core phenotype of ALS and constitutive expression of TDP-43 caused postnatal death. Objective: The study aimed to understand whether neurologic deficiency caused by mutant TDP-43 is dependent on its temporal expression. Method: Transgenic rats were established that express mutant human TDP-43 (M337V substitution) in neurons, then a Tet-off system was used to regulate its expression. Results: TDP-43 mutant transgenic rats developed significant weakness after the transgene was activated. Rats with expression of mutant TDP-43 at 30 days showed a more aggressive phenotype. More severe pathological changes in neurogenic atrophy were observed in these rats. Conclusion: Temporal expression of mutant TDP-43 in neurons promoted serious phenotype in rats. The dysfunction of TDP-43 had a profound impact on the development of motor neurons and skeletal muscles.