Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation.
Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation.
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DOI：
10.1083/jcb.139.5.1307
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发表时间：
1997-12-01
期刊：
影响因子：
--
通讯作者：
Lee VM
中科院分区：
文献类型：
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作者：
Zhang B;Tu P;Abtahian F;Trojanowski JQ;Lee VM
在家族性肌萎缩侧索硬化症 (FALS) 患者中发现，转基因小鼠表达编码人铜/锌超氧化物歧化酶 (SOD1) 的转基因，该酶具有 Gly93 → Ala (G93A) 突变，该小鼠会发展为一种快速进展且致命的运动神经元疾病 (MND)，与肌萎缩侧索硬化症 (ALS) 类似。在这些动物中还观察到了标志性的 ALS 损伤，例如高尔基体破碎和存活的脊髓运动神经元中富含神经丝 (NF) 的内含物以及该神经元群体的选择性变性。由于 SOD1 突变导致 MND 的机制仍然是个谜，因此我们想知道，在 MND 发生和进展的一系列小鼠中，运动神经元中的 NF 内含物是否会损害轴突运输，这些小鼠的转基因拷贝数比原始 G93A 少约 30%。与最初的 G93A 小鼠相比，这些小鼠的 MND 发作延迟，但它们出现了与最初的 G93A 小鼠相同的神经病理学异常，尽管时间点较晚，空泡更少，NF 内含物更多。定量蛋白质印迹分析显示，随着运动无力的出现，G93A 小鼠 L5 腹侧根中 NF 蛋白的水平逐渐降低，轴突口径也随之减小。到~200天时，这些小鼠腹侧根的快速和慢速轴突运输均受损，同时脆弱运动神经元的轴突和核周出现NF包涵体和空泡。这是 ALS 小鼠模型中轴突运输受损的首次证明，我们推断真正的 ALS 中也会出现类似的损伤。基于这些损伤与运动无力发作以及脆弱运动神经元中 NF 包涵体和空泡出现的时间相关性，后者损伤可能是 G93A 小鼠和具有 SOD1 突变的 FALS 患者运动神经元功能障碍和变性的近端原因。
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 ∼30% fewer copies of the transgene than the original G93A. 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 ∼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.