AGE-DEPENDENT PENETRANCE OF DISEASE IN A TRANSGENIC MOUSE MODEL OF FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS
AGE-DEPENDENT PENETRANCE OF DISEASE IN A TRANSGENIC MOUSE MODEL OF FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS
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DOI：
10.1006/mcne.1995.1027
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发表时间：
1995-08-01
影响因子：
3.5
通讯作者：
GURNEY, ME
中科院分区：
文献类型：
--
作者：
CHIU, AY;ZHAI, P;GURNEY, ME
Cu，Zn超氧化物歧化酶（SOD）的突变gly（93）-> ala在家族性肌萎缩侧索硬化症患者中发现，当在转基因小鼠中表达时，会导致运动神经元疾病。在命名为G1 H的小鼠系中研究了临床和病理疾病的进展。临床疾病开始于91 +/- 14日龄，伴有肢体轻微颤抖，随后在136 +/- 7日龄时瘫痪和死亡。病理变化开始的年龄与空泡来源于肿胀的线粒体积累在运动神经元。在临床疾病开始时（90天），支配肢体肌肉的躯体运动神经元显著死亡;在终末期疾病（136天）的小鼠显示出高达50%的颈部和腰部运动神经元损失。然而，无论是胸部或颅运动神经元显示明显的损失，尽管空泡的变化。自主运动神经元也不受影响。表达野生型人类Cu，Zn son的小鼠仍然没有疾病，表明突变通过功能获得引起神经元损失。因此，在该转基因模型中运动神经元疾病的年龄依赖性发病率是由于在选择的胆碱能神经元群体中病理损伤的逐渐积累。
The mutation gly(93) --> ala of Cu,Zn superoxide dismutase (SOD) is found in patients with familiar 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 son 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.