Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2
Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2
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DOI：
10.1523/jneurosci.2021-10.2010
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发表时间：
2010-09-08
影响因子：
5.3
通讯作者：
Kwak, Shin
中科院分区：
文献类型：
--
作者：
Hideyama, Takuto;Yamashita, Takenari;Kwak, Shin
GluR2是AMPA受体的一个亚基，其前mrna Q/R位点的腺苷通过作用于RNA 2的腺苷脱氨酶（ADAR2）转化为肌苷（a -to- i转化）。该位点A-to-I转换的失败会影响AMPA受体的多种特性，包括受体偶联离子通道的Ca2+通透性，从而在小鼠中诱发致命性癫痫（Brusa et al., 1995; Feldmeyer et al., 1999）。此外，GluR2 Q/R位点编辑效率低下是一种疾病特异性的分子功能障碍，存在于散发性肌萎缩侧索硬化症（ALS）患者的运动神经元中（Kawahara et al., 2004）。在这里，我们使用Cre/loxP系统生成了ADAR2基因有条件靶向运动神经元的转基因小鼠（命名为AR2）。这些AR2小鼠表现出与脊髓和颅运动神经核中adar2缺陷运动神经元的缓慢死亡相称的运动功能下降。值得注意的是，尽管GluR2 Q/R位点编辑显著减少，但在ALS中经常避免变性的动眼神经核中的神经元数量并未减少。当携带内源性GluR2等位基因的小鼠被改造为表达没有ADAR2活性的编辑GluR2时，AR2小鼠的所有细胞和表型变化都被阻止（Higuchi et al., 2000）。因此，ADAR2活性的丧失导致AMPA受体介导的运动神经元死亡。
GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca2+ permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.