Pathological study of mutant SOD1 (G93A and H46R) transgenic mice

我们通过电镜和免疫电镜观察了G93A突变SOD1基因转基因（Tg）小鼠的脊髓，以阐明该动物模型家族性ALS的发病机制。(1)与对照组相比，Tg小鼠比对照组更频繁地观察到直接从正常前角细胞发出的近端轴突，神经丝增加，或者线粒体增加（在较小程度上），即使在症状前的早期阶段，这种频率也随着时间的推移而增加。与近端轴突直接相连的运动神经元体未见神经丝或线粒体的异常堆积。(2)前根出口区、前根、前角神经球内可见大小不等的空泡。线粒体膜间隙经常空泡化。在高度空泡化的线粒体中，空泡空间充满粒状或无定形物质。SOD1和泛素决定因子都定位于空泡线粒体。空泡线粒体仅在轴突中观察到，而在近端树突或体细胞中没有观察到。(3) sod1和泛素阳性聚集物和路易体样包裹体在Tg小鼠的神经过程中经常出现，包括脊髓样肿胀的轴突和一些剩余的前角神经元。聚集体的大小和频率随着时间的推移而增加。这些聚集体几乎都是由相互交织的中间细丝（直径约10-15 nm）组成，显示出高水平的人类sod1和泛素免疫金标记。聚集体经常出现，主要出现在包括近轴突在内的前角的神经元突起中，而在体细胞和树突中则相当罕见。因此，近端轴突运输障碍可能在该模型的病理机制中起关键作用。

We electronmicroscopically and immunoelectronmicroscopically investigated the spinal cords of transgenic(Tg) mice with a G93A mutant SOD1 gene to elucidate the pathomechanisms of this animal model for familial ALS.(1)Proximal axons directly emanating from normal-looking anterior horn cells with increased neurofilaments or, to a lesser extent, increased mitochondria, were more frequently observed in Tg mice than in the controls, even at the early presymptomatic stage, and the frequency increased with time. The somata of motor neurons directly connected with proximal axons did not exhibit any abnormal accumulation of neurofilaments or mitochondria.(2)Vacuoles of various sizes were observed in the anterior root exit zone, anterior root, and in the neuropils of the anterior horn. The intermembrane space of mitochondria was frequently vacuolated. In mitochodria with advanced vacuolation, the vacuolar space was filled with a granular or amorphous substance. Both SOD1 and ubiquitin determinants were localized in vacuolated mitochondria. The vacuolated mitochondria were exclusively observed in the axons, and not in proximal dendrites or somata.(3)SOD1-and ubiquitin-positive aggregates and Lewy body-like inclusions were frequently demonstrated in the neuronal processes including cord-like swollen axons and in some remaining anterior horn neurons in Tg mice. The aggregates increased in size and frequency with time. The aggregates almost always consisted basically of interwoven intermediate filaments (about 10-15 nm in diameter), showing a high level of human SOD1-and ubiquitin-immunogold labeling. Aggregates were frequently shown, predominating in the neuronal processes of the anterior horns including the proximal axons, whereas they were rather rare in the somata and dendrites.Thus, impairment of proximal axonal transport may play a pivotal role in the pathomechanism of this model.