突变型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。
Temporal Expression of Mutant TDP-43 Correlates with Early Amyotrophic Lateral Sclerosis Phenotype and Motor Weakness.
作者信息
Chen Qihua, Zhou Jinxia, Huang Cao, Huang Bo, Bi Fangfang, Zhou Hongxia, Xiao Bo
机构信息
Department of Neurology, Xiangya Hospital of Central South University, Changsha 410008, China.
Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, United States.
出版信息
Curr Neurovasc Res. 2018;15(1):3-9. doi: 10.2174/1567202615666180109161541.
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.
背景
突变型反式作用应答DNA结合蛋白（TDP-43）与肌萎缩侧索硬化症（ALS）的遗传形式密切相关。TDP-43转基因大鼠能够重现ALS的核心表型，且TDP-43的组成型表达会导致出生后死亡。
目的
本研究旨在了解突变型TDP-43引起的神经功能缺陷是否依赖于其时间表达。
方法
构建在神经元中表达突变型人TDP-43（M337V替换）的转基因大鼠，然后使用四环素调控系统来调节其表达。
结果
转基因激活后，TDP-43突变转基因大鼠出现明显的肌无力。在30天时表达突变型TDP-43的大鼠表现出更具侵袭性的表型。在这些大鼠中观察到神经源性萎缩更严重的病理变化。
结论
神经元中突变型TDP-43的时间表达促进了大鼠严重表型的出现。TDP-43功能障碍对运动神经元和骨骼肌的发育产生了深远影响。
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