Collard J F, Côté F, Julien J P
Centre for Research in Neurosciences, McGill University, Montreal General Hospital Research Institute, Canada.
Nature. 1995 May 4;375(6526):61-4. doi: 10.1038/375061a0.
Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons, characterized by depositions of neurofilaments in the perikarya and proximal axons. The pathogenesis of ALS remains poorly understood, but two lines of evidence suggest that neurofilament accumulation may play a causal role. First, transgenic mice that overexpress neurofilament proteins show motor neuron degeneration and, second, variant alleles of the neurofilament heavy-subunit gene (NF-H) have been found in some human ALS patients. To investigate how disorganized neurofilaments might cause neurodegeneration, we examined axonal transport of newly synthesized proteins in mice that overexpress the human NF-H gene. We observed dramatic defects of axonal transport, not only of neurofilament proteins but also of other proteins, including tubulin and actin. Ultrastructural analysis revealed a paucity of cytoskeletal elements, smooth endoplasmic reticulum and especially mitochondria in the degenerating axons. We therefore propose that the neurofilament accumulations observed in these mice cause axonal degeneration by impeding the transport of components required for axonal maintenance, and that a similar mechanism may account for the pathogenesis of ALS in human patients.
肌萎缩侧索硬化症（ALS）是一种运动神经元的退行性疾病，其特征是神经丝在神经元胞体和近端轴突中沉积。ALS的发病机制仍知之甚少，但有两条证据表明神经丝积累可能起因果作用。第一，过度表达神经丝蛋白的转基因小鼠表现出运动神经元退化；第二，在一些人类ALS患者中发现了神经丝重链亚基基因（NF-H）的变异等位基因。为了研究紊乱的神经丝如何导致神经退行性变，我们检测了过度表达人类NF-H基因的小鼠中新合成蛋白质的轴突运输。我们观察到轴突运输存在显著缺陷，不仅神经丝蛋白，其他蛋白质包括微管蛋白和肌动蛋白也有缺陷。超微结构分析显示，在退化的轴突中，细胞骨架成分、滑面内质网尤其是线粒体数量稀少。因此，我们提出在这些小鼠中观察到的神经丝积累通过阻碍轴突维持所需成分的运输导致轴突退化，并且类似机制可能解释人类患者ALS的发病机制。
