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

我们用电镜和免疫电镜研究了具有G93 A突变SOD 1基因的转基因（Tg）小鼠的脊髓，以阐明这种家族性ALS动物模型的病理机制。（1）与对照组相比，在Tg小鼠中观察到的直接从正常前角细胞发出的近端轴突增加了神经丝，或在较小程度上增加了线粒体，即使在症状前早期，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胞体没有表现出任何神经丝或线粒体的异常积累。（2）在前根出口区、前根和前角神经柱内可见大小不等的神经孔。线粒体膜间隙常空泡化。在线粒体与先进的空泡，空泡空间充满了颗粒状或无定形物质。SOD 1和泛素决定簇均定位于空泡化的线粒体。空泡化的线粒体仅在轴突中观察到，而不是在近端树突或胞体中。（3）在Tg小鼠神经元突起中，包括索状肿胀轴突和部分残存的前角神经元中，常可见SOD 1和泛素阳性聚集体和Lewy小体样包涵体。随着时间的推移，聚集体的大小和频率增加。聚集体几乎总是基本上由交织的中间丝（直径约10-15 nm）组成，显示出高水平的人SOD 1-和泛素-免疫金标记。聚集体在前角的神经突起中占优势，包括近端轴突，而在胞体和树突中则很少，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.