Chiu A Y, Zhai P, Dal Canto M C, Peters T M, Kwon Y W, Prattis S M, Gurney M E
Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Mol Cell Neurosci. 1995 Aug;6(4):349-62. doi: 10.1006/mcne.1995.1027.
The mutation gly93-->ala of Cu,Zn superoxide dismutase (SOD) is found in patients with familial amyotrophic lateral sclerosis and causes motor neuron disease when expressed in transgenic mice. The progression of clinical and pathological disease was studied in a line of mice designated G1H. Clinical disease started at 91 +/- 14 days of age with fine shaking of the limbs, followed by paralysis and death by 136 +/- 7 days of age. Pathological changes begin by 37 days of age with vacuoles derived from swollen mitochondria accumulating in motor neurons. At the onset of clinical disease (90 days), significant death of somatic motor neurons innervating limb muscles has occurred; mice at end-stage disease (136 days) show up to 50% loss of cervical and lumbar motor neurons. However, neither thoracic nor cranial motor neurons show appreciable loss despite vacuolar changes. Autonomic motor neurons also are not affected. Mice that express wild-type human Cu,Zn SOD remain free of disease, indicating that mutations cause neuron loss by a gain-of-function. Thus, the age-dependent penetrance of motor neuron disease in this transgenic model is due to the gradual accumulation of pathological damage in select populations of cholinergic neurons.
在患有家族性肌萎缩侧索硬化症的患者中发现了铜锌超氧化物歧化酶（SOD）的gly93→ala突变，该突变在转基因小鼠中表达时会引发运动神经元疾病。对一组名为G1H的小鼠的临床和病理疾病进展进行了研究。临床疾病在91±14日龄时开始，表现为四肢轻微颤抖，随后出现瘫痪，并在136±7日龄时死亡。病理变化在37日龄时开始，运动神经元中出现源自肿胀线粒体的空泡。在临床疾病发作时（90天），支配肢体肌肉的躯体运动神经元已出现明显死亡；处于疾病终末期（136天）的小鼠，其颈段和腰段运动神经元损失高达50%。然而，尽管有液泡变化，胸段和颅段运动神经元并未出现明显损失。自主运动神经元也未受影响。表达野生型人铜锌SOD的小鼠未患疾病，这表明突变通过功能获得导致神经元损失。因此，在这个转基因模型中，运动神经元疾病的年龄依赖性外显率是由于胆碱能神经元特定群体中病理损伤的逐渐积累所致。
