A robust TDP-43 knock-in mouse model of ALS
A robust TDP-43 knock-in mouse model of ALS
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DOI：
10.1186/s40478-020-0881-5
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发表时间：
2020-01-21
影响因子：
7.1
通讯作者：
Shen, Che-Kun James
中科院分区：
文献类型：
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作者：
Huang, Shih-Ling;Wu, Lien-Szu;Shen, Che-Kun James
肌萎缩侧索硬化症（ALS）是一种致命的，成人发病的运动神经元退行性疾病。超过95%的肌萎缩侧索硬化症（ALS）患者的患病脊髓运动神经元的特征在于RNA/DNA结合蛋白TDP-43（ALS-TDP）的错误代谢，特别是该蛋白质的胞质聚集体的存在。用于ALS-TDP的基础或翻译研究的大多数可用的小鼠模型是基于TDP-43蛋白的转基因过表达。在这里，我们报告的产生和表征的小鼠线轴承同源敲入fALS相关的突变A315 T和sALS相关的突变N390 D，分别。值得注意的是，杂合TDP-43（N390 D/+）小鼠而非TDP-43（A315 T/+）小鼠的杂合小鼠在分子、细胞和行为水平上发展出全谱的ALS-TDP样病理。对突变小鼠和源自其胚胎干（ES）细胞的脊髓运动神经元（MN）的比较分析表明，不同的ALS相关TDP-43突变具有关键的ALS引起能力和致病途径，可能由其遗传背景和环境因素修饰。从机制上讲，我们确定了脊髓Bcl-2前mRNA的异常RNA剪接和随之而来的自噬负调节因子Bcl-2的增加，这与TDP-43（N390 D/+）小鼠脊髓和源自其ES细胞的脊髓MN中TDP-43（与ALS-TDP发病机制相关的早期事件之一）的进行性增加相关并由其引起。TDP-43（N390 D/+）基因敲入小鼠似乎是用于ALS-TDP的基础以及转化研究的理想啮齿动物模型。
Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS- TDP.