【摘要】 肌萎缩性侧索硬化症(ALS)是以上下两级运动神经元进行性丢失为特征的神经系统变性疾病,是运动神经元病(MND)中最常见的类型。运动神经元中的病理性TDP-43是ALS的病理特征。此外,散发性ALS运动神经元中作用于RNA的次黄嘌呤腺苷脱氢酶(ADAR2)减少、具有未经编辑Q/R位点的谷氨酸受体2(GluR2)表达增加,α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)属性受影响,Ca2+通透性增加,Ca2+流入胞质增加导致神经元死亡。ALS运动神经元死亡包含病理性TDP-43和ADAR2活性下降,两种病理变化可能在细胞死亡中存在一定联系。ADAR2 mRNA是TDP-43蛋白的靶RNA,TDP-43蛋白在ADAR2的表达中起调节作用。近年来,研究者探讨ALS的基因治疗可能性:动物实验结果提示,外周静脉给予9型腺相关病毒载体(AAV9),可上调鼠运动神经元ADAR2,引发外源性ADAR2在中枢神经元表达,从而有效防治运动功能障碍。运动神经元的获救可能与TDP-43基因的正常表达有关。AAV9介导的ADAR2基因植入可能为ALS的基因治疗提供新的前景。更多还原

【Abstract】 Amyotrophic lateral sclerosis(ALS) is the most common adult-onset nervous system degenerative disease, characterized by the progressive loss of upper and lower motor neurons. TDP-43 pathology in motor neurons is a hallmark of ALS. In addition, the reduced expression of an RNA editing enzyme, adenosine dehydrogenase acting on RNA2(ADAR2), increases the expression of GluA2 with an unedited Q/ 357R site in the motor neurons of patients with sporadic ALS. The change in amino acid residue at the Q/R site of GluR2 results in marked alterations in channel properties of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor(AMPAR), increasing Ca2+ permeability and increasing Ca2+ influx, play a key role in the death of motor neurons. ADAR2 mRNA is a target RNA for TDP-43 and TDP-43 plays a regulatory role of in the expression of ADAR2. Recently, scholars explored the possibility of gene therapy for ALS by up-regulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9(AAV9) vector that provides gene delivery to a wide array of central neurons after peripheral administration, caused expression of exogenous ADAR2 in the central neurons and effectively prevented progressive motor dysfunction. AAV9-ADAR2 rescued the motor neurons from death by normalizing TDP-43 expression. This AAV9-mediated ADAR2 gene delivery may therefore enable the development of a gene therapy for ALS.更多还原