Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis.
Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis.
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DOI：
10.1038/gt.2014.101
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发表时间：
2015-01
期刊：
影响因子：
5.1
通讯作者：
Klein RL
中科院分区：
文献类型：
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作者：
Jackson KL;Dayton RD;Orchard EA;Ju S;Ringe D;Petsko GA;Maquat LE;Klein RL
无义介导的mRNA衰变（NMD）是一种需要上移蛋白1 （UPF1）的RNA监视机制。这项研究表明，人类UPF1在基于肌萎缩性侧索硬化症（ALS）相关蛋白TDP-43（交互反应dna结合蛋白43 kDa）的大鼠瘫痪模型中发挥保护作用。利用腺相关病毒载体（AAV9）在大鼠脊髓中表达TDP-43，诱导再现性肢体瘫痪，再现ALS的瘫痪。我们选择UPF1进行基于酵母基因筛选的治疗性测试。人TDP-43或人UPF1在脊髓中的表达被滴定到低于各自内源性水平的两倍。AAV9人mycUPF1明显改善了表达TDP-43的大鼠的整体运动评分。与空载体组和绿色荧光蛋白载体对照组相比，mycUPF1的基因治疗效果具有特异性和可重复性。基因疗法维持了大鼠的前肢运动功能，否则会变成四肢瘫痪。这项工作有助于验证UPF1作为ALS和其他tdp -43相关疾病的新疗法，并可能暗示UPF1和NMD参与潜在的疾病机制。
Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that requires upframeshift protein 1 (UPF1). This study demonstrates that human UPF1 exerts protective effects in a rat paralysis model based on the amyotrophic lateral sclerosis (ALS)-associated protein, TDP-43 (transactive response DNA-binding protein 43 kDa). An adeno-associated virus vector (AAV9) was used to express TDP-43 throughout the spinal cord of rats, inducing reproducible limb paralysis, to recapitulate the paralysis in ALS. We selected UPF1 for therapeutic testing based on a genetic screen in yeast. The expression of human TDP-43 or human UPF1 in the spinal cord was titrated to less than twofold over the respective endogenous level. AAV9 human mycUPF1 clearly improved overall motor scores in rats also expressing TDP-43. The gene therapy effect of mycUPF1 was specific and reproducible compared with groups receiving either empty vector or green fluorescent protein vector controls. The gene therapy maintained forelimb motor function in rats that would otherwise become quadriplegic. This work helps validate UPF1 as a novel therapeutic for ALS and other TDP-43-related diseases and may implicate UPF1 and NMD involvement in the underlying disease mechanisms.