Zhang B, Tu P, Abtahian F, Trojanowski J Q, Lee V M
The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Cell Biol. 1997 Dec 1;139(5):1307-15. doi: 10.1083/jcb.139.5.1307.
Mice engineered to express a transgene encoding a human Cu/Zn superoxide dismutase (SOD1) with a Gly93 --> Ala (G93A) mutation found in patients who succumb to familial amyotrophic lateral sclerosis (FALS) develop a rapidly progressive and fatal motor neuron disease (MND) similar to amyotrophic lateral sclerosis (ALS). Hallmark ALS lesions such as fragmentation of the Golgi apparatus and neurofilament (NF)-rich inclusions in surviving spinal cord motor neurons as well as the selective degeneration of this population of neurons were also observed in these animals. Since the mechanism whereby mutations in SOD1 lead to MND remains enigmatic, we asked whether NF inclusions in motor neurons compromise axonal transport during the onset and progression of MND in a line of mice that contained approximately 30% fewer copies of the transgene than the original G93A (Gurney et al., 1994). The onset of MND was delayed in these mice compared to the original G93A mice, but they developed the same neuropathologic abnormalities seen in the original G93A mice, albeit at a later time point with fewer vacuoles and more NF inclusions. Quantitative Western blot analyses showed a progressive decrease in the level of NF proteins in the L5 ventral roots of G93A mice and a concomitant reduction in axon caliber with the onset of motor weakness. By approximately 200 d, both fast and slow axonal transports were impaired in the ventral roots of these mice coincidental with the appearance of NF inclusions and vacuoles in the axons and perikarya of vulnerable motor neurons. This is the first demonstration of impaired axonal transport in a mouse model of ALS, and we infer that similar impairments occur in authentic ALS. Based on the temporal correlation of these impairments with the onset of motor weakness and the appearance of NF inclusions and vacuoles in vulnerable motor neurons, the latter lesions may be the proximal cause of motor neuron dysfunction and degeneration in the G93A mice and in FALS patients with SOD1 mutations.
在死于家族性肌萎缩侧索硬化症（FALS）的患者中发现的携带甘氨酸93突变为丙氨酸（G93A）的人类铜/锌超氧化物歧化酶（SOD1）转基因的工程小鼠，会发展出一种与肌萎缩侧索硬化症（ALS）相似的快速进展且致命的运动神经元疾病（MND）。在这些动物中还观察到了典型的ALS病变，如高尔基体碎片化以及存活的脊髓运动神经元中富含神经丝（NF）的包涵体，以及这群神经元的选择性退化。由于SOD1突变导致MND的机制仍然不明，我们在一组转基因拷贝数比原始G93A小鼠少约30%的小鼠品系中研究运动神经元中的NF包涵体在MND发病和进展过程中是否会损害轴突运输（Gurney等人，1994年）。与原始G93A小鼠相比，这些小鼠的MND发病延迟，但它们出现了与原始G93A小鼠相同的神经病理学异常，尽管时间点较晚，空泡较少且NF包涵体较多。定量蛋白质免疫印迹分析显示，随着运动无力的出现，G93A小鼠L5腹根中NF蛋白水平逐渐降低，同时轴突直径减小。到大约200天时，这些小鼠腹根中的快速和慢速轴突运输均受损，这与易损运动神经元的轴突和胞体中出现NF包涵体和空泡同时发生。这是在ALS小鼠模型中首次证明轴突运输受损，我们推断在真正的ALS中也会发生类似的损伤。基于这些损伤与运动无力的发作以及易损运动神经元中NF包涵体和空泡的出现之间的时间相关性，后一种病变可能是G93A小鼠和携带SOD1突变的FALS患者中运动神经元功能障碍和退化的近端原因。
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