AMPA receptor-mediated neuronal death in sporadic ALS
AMPA receptor-mediated neuronal death in sporadic ALS
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DOI：
10.1111/j.1440-1789.2009.01090.x
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发表时间：
2010-04-01
期刊：
影响因子：
2.3
通讯作者：
Aizawa, Hitoshi
中科院分区：
文献类型：
--
作者：
Kwak, Shin;Hideyama, Takuto;Aizawa, Hitoshi
α -氨基-3-羟基-5-甲基-4-异恶唑丙酸盐（AMPA）受体介导的兴奋性毒性被认为在肌萎缩侧索硬化症（ALS）运动神经元死亡中起作用。我们证明，在散发性ALS患者的尸检获得的脊髓运动神经元中，谷氨酰胺/精氨酸（Q/R）位点的GluR2 mRNA的RNA编辑减少，但在小脑浦肯野细胞中没有。这种分子变化发生在各种表型的散发性ALS患者的运动神经元中，但不发生在其他神经退行性疾病患者的退行性神经元中，包括sod1相关的家族性ALS。由于GluR2 Q/R位点编辑是由作用于RNA 2的腺苷脱氨酶（adenosine deaminase on RNA 2, ADAR2）特异性催化的，因此ADAR2活性的调控机制很可能在散发性ALS的运动神经元中不起作用。事实上，与正常对照组相比，散发性ALS患者脊髓腹侧灰质中ADAR2的表达水平显著降低。可能是运动神经元中ADAR2选择性低活性诱导GluR2 Q/R位点编辑缺陷，从而导致散发性ALS的神经元死亡。因此，在运动神经元死亡的多种不同分子机制中，可能是Q/R位点未编辑的含Ca2+可渗透glur2的AMPA受体比例的增加引发了散发性ALS中运动神经元的死亡。为此，运动神经元中ADAR2活性的正常化可能成为散发性ALS的治疗策略。
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated excitotoxicity has been proposed to play a role in death of motor neurons in amyotrophic lateral sclerosis (ALS). We demonstrated that RNA editing of GluR2 mRNA at the glutamine/arginine (Q/R) site was decreased in autopsy-obtained spinal motor neurons, but not in cerebellar Purkinje cells, of patients with sporadic ALS. This molecular change occurs in motor neurons of sporadic ALS cases with various phenotypes, but not in degenerating neurons of patients with other neurodegenerative diseases, including SOD1-associated familial ALS. Because GluR2 Q/R site-editing is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2), it is likely that regulatory mechanism of ADAR2 activity does not work well in the motor neurons of sporadic ALS. Indeed, ADAR2 expression level was significantly decreased in the spinal ventral gray matter of sporadic ALS as compared to normal control subjects. It is likely that ADAR2 underactivity selective in motor neurons induced deficient GluR2 Q/R site-editing, which results in the neuronal death of sporadic ALS. Thus, among multiple different molecular mechanisms underlying death of motor neurons, it is likely that an increase of the proportion of Q/R site-unedited GluR2-containing Ca2+-permeable AMPA receptors initiates the death of motor neurons in sporadic ALS. To this end, normalization of ADAR2 activity in motor neurons may become a therapeutic strategy for sporadic ALS.