Yamanaka Koji, Miller Timothy M, McAlonis-Downes Melissa, Chun Seung Joo, Cleveland Don W
Ludwig Institute for Cancer Research and Department of Medicine and Neurosciences, University of California, San Diego, La Jolla, 92093-0670, USA.
Ann Neurol. 2006 Jul;60(1):95-104. doi: 10.1002/ana.20888.
Homozygous mutation in the ALS2 gene and the resulting loss of the guanine exchange factor activity of the ALS2 protein is causative for autosomal recessive early-onset motor neuron disease that is thought to predominantly affect upper motor neurons. The goal of this study was to elucidate how the motor system is affected by the deletion of ALS2.
ALS2-deficient mice were generated by gene targeting. Motor function and upper and lower motor neuron pathology were examined in ALS2-deficient mice and in mutant superoxide dismutase 1 (SOD1) mice that develop ALS-like disease from expression of an ALS-linked mutation in SOD1.
ALS2-deficient mice demonstrated progressive axonal degeneration in the lateral spinal cord that is also prominent in mutant SOD1 mice. Despite the vulnerability of these spinal axons, lower motor neurons in ALS2-deficient mice were preserved. Behavioral studies demonstrated slowed movement without muscle weakness in ALS2(-/-) mice, consistent with upper motor neuron defects that lead to spasticity in humans.
The combined evidence from mice and humans shows that deficiency in ALS2 causes an upper motor neuron disease that in humans closely resembles a severe form of hereditary spastic paralysis, and that is quite distinct from amyotrophic lateral sclerosis.
ALS2基因的纯合突变以及由此导致的ALS2蛋白鸟嘌呤交换因子活性丧失是常染色体隐性早发性运动神经元疾病的病因，该疾病被认为主要影响上运动神经元。本研究的目的是阐明ALS2缺失如何影响运动系统。
通过基因靶向技术构建ALS2缺陷小鼠。对ALS2缺陷小鼠以及因超氧化物歧化酶1（SOD1）中与肌萎缩侧索硬化症（ALS）相关的突变表达而患类似ALS疾病的突变型SOD1小鼠的运动功能以及上、下运动神经元病理学进行检查。
ALS2缺陷小鼠在脊髓外侧表现出进行性轴突变性，这在突变型SOD1小鼠中也很明显。尽管这些脊髓轴突易受损，但ALS2缺陷小鼠的下运动神经元得以保留。行为学研究表明，ALS2（-/-）小鼠运动迟缓但无肌肉无力，这与人类中导致痉挛的上运动神经元缺陷一致。
来自小鼠和人类的综合证据表明，ALS2缺陷会导致一种上运动神经元疾病，在人类中这种疾病与严重形式的遗传性痉挛性截瘫非常相似，且与肌萎缩侧索硬化症截然不同。
