Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase‐1 mutation-猫眼课题宝

超氧化物歧化酶-1突变家族性肌萎缩侧索硬化症转基因小鼠模型

DOI：

10.1111/j.1440-1789.2001.00361.x

发表时间：

2001

期刊：

Neuropathology

影响因子：

2.3

通讯作者：

中科院分区：

医学4区

文献类型：

作者：

N. Shibata

家族性肌萎缩侧索硬化症(ALS)是通过表达可在家族性ALS患者中检测到的SOD1突变形式的转基因小鼠进行临床病理复制的。与SOD1突变相关的运动神经元变性被认为是由于突变的SOD1引起的一种新的神经毒性，而不是该酶活性的降低，基于SOD1突变的家族性ALS及其转基因小鼠模型的常染色体显性遗传传递，ALS患者的临床严重程度与酶活性无关，SOD1基因敲除或野生型SOD1过表达小鼠中没有类似ALS的疾病，以及突变的SOD1转基因小鼠的临床病理严重程度取决于转基因拷贝数。已提出的运动神经元退化的机制包括氧化损伤、过氧亚硝酸盐毒性、细胞骨架紊乱、谷氨酸兴奋毒性、钙稳态紊乱、SOD1聚集、羰基应激和细胞凋亡。突变型SOD1转基因小鼠高表达的神经纤维和运动神经元内出现空泡，表明线粒体和内质网的氧化损伤增加，而在小鼠或家族性ALS患者的低表达中则没有，这表明突变的SOD1在小鼠中的过表达可能会增加该酶产生的氧化应激。因此，携带少量突变型SOD1基因的转基因小鼠将为SOD1突变型家族性ALS提供一个有益的动物模型。这样的模型将有助于阐明该病的发病机制，并建立新的治疗药物。

Familial amyotrophic lateral sclerosis (ALS) with mutations in the gene for superoxide dismutase‐1 (SOD1) is clinicopathologically reproduced by transgenic mice expressing mutant forms of SOD1 detectable in familial ALS patients. Motor neuron degeneration associated with SOD1 mutation has been thought to result from a novel neurotoxicity of mutant SOD1, but not from a reduction in activity of this enzyme, based on autosomal dominant transmission of SOD1 mutant familial ALS and its transgenic mouse model, clinical severity of the ALS patients independent to enzyme activity, no ALS‐like disease in SOD1 knockout or wild‐type SOD1‐over‐expressing mice, and clinicopathological severity of mutant SOD1 transgenic mice dependent on transgene copy numbers. Proposed mechanisms of motor neuron de‐generation such as oxidative injury, peroxynitrite toxicity, cytoskeletal disorganization, glutamate excitotoxicity, disrupted calcium homeostasis, SOD1 aggregation, car‐bonyl stress and apoptosis have been discussed. Intracy‐toplasmic vacuoles, indicative of increased oxidative damage to the mitochondria and endoplasmic reticulum, in the neuropil and motor neurons appear in high expressors of mutant SOD1 transgenic mice but not in low expressors of the mice or familial ALS patients, suggesting that overexpression of mutant SOD1 in mice may enhance oxidative stress generation from this enzyme. Thus, transgenic mice carrying small transgene copy numbers of mutant SOD1 would provide a beneficial animal model for SOD1 mutant familial ALS. Such a model would contribute to elucidating the pathomechanism of this disease and establishing new therapeutic agents.