谷氨酸受体2（glutamate receptor A2,GluA2）Q/R部位编辑率降低以及相关的RNA2的次黄嘌呤腺苷脱氨酶（adenosine deaminase acting on RNA2,ADAR2）的异常与病理性反式激活应答DNA结合蛋白43（transactivation response DNA-binding protein 43-kD,TDP-43）可同时发生在肌萎缩侧索硬化（amyotrophic lateral sclerosis,ALS）患者的运动神经元中,提示在ALS患者中,这些异常分子病变之间可能存在关联。条件性敲除ADAR2基因的ALS小鼠可表现为运动神经元的缓慢死亡。因为缺乏ADAR2可引起TDP-43的异常分布和聚集,引发神经细胞毒性,继而加速运动神经元变性及死亡。本文总结了GluA2 Q/R部位RNA无效编辑的规律和病理性TDP-43在ALS发病中的作用,并讨论了可能影响ADAR2介导的RNA无效编辑的相关因素,以期为研发新的ALS治疗方法提供参考依据。
Abstract
Inefficient glutamate receptor A2 (GluA2) Q/R site-RNA editing and related downregulation of adenosine deaminase acting on RNA2 (ADAR2) expression as well as pathological transactivation response DNA-binding protein 43-kD (TDP-43) can simultaneously occur in the same motor neurons in patients with amyotrophic lateral sclerosis (ALS), suggesting that there may be an association among these molecular abnormalities in ALS patients. The animal experiment has found that after knock-down of ADAR2 gene, the motor neurons of the rats showed a chronic death. The abnormal mislocalization and aggregation of TDP-43 fragments induced by ADAR2 difficiency results in nerve cell toxicity, then accelerating the degeneration and death of the motor neurons. This paper summarizes the role of inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in sporadic ALS, and discusses the possible influencing factors associated with inefficient RNA editing mediated by ADAR2, hoping to provide useful information to develop a novel therapeutic strategy for ALS.
关键词
肌萎缩侧索硬化 /
谷氨酸受体 /
TDP-43 /
钙蛋白酶 /
发病机制
Key words
Amyotrophic lateral sclerosis /
Glutamate receptor /
TDP-43 /
Calpain /
Pathogenic mechanism
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基金
国家自然科学基金面上项目（编号：81373619）
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