Shin Kwak
Department of Neurology, Graduate School of Medicine, The University of Tokyo.
Rinsho Shinkeigaku. 2005 Nov;45(11):982-4.
AMPA receptor-mediated neuronal death is initiated by exaggerated Ca2+ influx through AMPA receptor channels, and the Ca2+ permeability of the AMPA receptor ion channel depends strongly upon the presence or absence in its composition of an edited GluR2 subunit whose glutamine (Q) residue is substituted by arginine (R) at the Q/R site due to RNA editing. The pivotal role of the RNA editing at the GluR2 Q/R site in neuronal death has been clearly demonstrated in animal experiments and its deficiency is a direct cause of neuronal death. We demonstrated that the editing efficiency at the GluR2 mRNA Q/R site varied greatly, from 0% to 100%, among the single motoneurons of each individual with ALS, whereas it remained 100% among those of normal controls. In addition, the editing efficiency was more than 99% in the cerebellar Purkinje cells of ALS, spinocerebellar degeneration and normal control groups. By contrast, there was no significant difference as to both the amount and the proportion to total GluRs mRNA of GluR2 mRNA between normal and ALS motoneurons. Thus, marked GluR2 underediting in ALS motoneurons occurs in a disease specific and region selective manner, and may be closely relevant to ALS etiology.
AMPA受体介导的神经元死亡是由通过AMPA受体通道的过度Ca2+内流引发的，而AMPA受体离子通道的Ca2+通透性在很大程度上取决于其组成中是否存在经编辑的GluR2亚基。由于RNA编辑，该亚基在Q/R位点的谷氨酰胺（Q）残基被精氨酸（R）取代。GluR2 Q/R位点的RNA编辑在神经元死亡中的关键作用已在动物实验中得到明确证实，其缺陷是神经元死亡的直接原因。我们证明，在肌萎缩侧索硬化症（ALS）患者的单个运动神经元中，GluR2 mRNA Q/R位点的编辑效率差异很大，从0%到100%不等，而在正常对照组的运动神经元中，编辑效率保持在100%。此外，在ALS、脊髓小脑变性和正常对照组的小脑浦肯野细胞中，编辑效率超过99%。相比之下，正常运动神经元和ALS运动神经元之间，GluR2 mRNA的量及其占总GluRs mRNA的比例均无显著差异。因此，ALS运动神经元中明显的GluR2编辑不足以疾病特异性和区域选择性的方式发生，可能与ALS的病因密切相关。
