Sasaki Shoichi, Warita Hitoshi, Abe Koji, Iwata Makoto
Department of Neurology, Neurological Institute, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, 162-8666 Tokyo, Japan.
Acta Neuropathol. 2004 May;107(5):452-60. doi: 10.1007/s00401-004-0838-y. Epub 2004 Mar 17.
The purpose of this study was to determine whether slow axonal transport of neurofilaments (NFs) is impaired in the spinal cord of G93A Cu/Zn superoxide dismutase (SOD1) mutant transgenic mice expressing a relatively low mutant protein (gene copy 10) and, if so, how the impairment occurs in this animal model. Transgenic mice were killed at the ages of 24, 28 and 32 weeks, and the cervical and lumbar spinal cords were examined under an electron microscope. Age-matched non-transgenic wild-type mice served as controls. At 24 weeks (early presymptomatic stage), anterior horn cells were well preserved. The earliest morphological changes were mild vacuolar changes in the neuronal processes, particularly in proximal axons. At 28 weeks (late presymptomatic stage), mild neuronal loss of anterior horn neurons was observed. Vacuolar changes were more prominent in the proximal axons, including swollen axons (spheroids) and neuropils of the anterior horns. Vacuoles in the axons were frequently large enough to occupy almost the entire axonal caliber. The anterior roots were degenerative, showing vacuolar changes and myelin ovoids. Lewy body-like inclusions (LIs) consisting of filaments thicker than NFs (about 1.5 times larger in diameter) were frequently demonstrated in the neuronal processes including swollen axons (spheroids) and occasionally in the somata. At 32 weeks (symptomatic stage), the anterior horns showed a moderate to severe neuronal loss accompanied by prominent astrogliosis. Cord-like swollen axons consisting of accumulated NFs and many neurofilamentous accumulations were frequently observed in the anterior horn. Vacuolar changes were less prominent or disappeared in the neuropils of the anterior horns and the anterior roots, whereas LIs were frequently demonstrated within the neuronal processes including the cord-like swollen axons. In the anterior roots, degenerative changes such as marked fiber loss and frequent myelin ovoids were remarkable. No accumulation of NFs or mitochondrial vacuolation was detected in somata or proximal dendrites at any stage. These findings suggest that the slow component of axonal transport in the proximal axons is impaired at an early stage in this transgenic mouse model, and that the impairment is probably caused by a mechanical impediment of NFs, or by the accumulation of NFs in the proximal axon, as a result of the obstruction of the axonal flow that initially occurs by vacuolar changes, and is later exacerbated by accumulation of LIs.
本研究的目的是确定在表达相对低水平突变蛋白（基因拷贝数为10）的G93A铜锌超氧化物歧化酶（SOD1）突变转基因小鼠的脊髓中，神经丝（NFs）的轴突慢速运输是否受损；如果受损，在该动物模型中这种损伤是如何发生的。在24、28和32周龄时处死转基因小鼠，并在电子显微镜下检查颈段和腰段脊髓。年龄匹配的非转基因野生型小鼠作为对照。在24周（症状前期早期），前角细胞保存良好。最早的形态学变化是神经元突起，特别是近端轴突出现轻度空泡样改变。在28周（症状前期晚期），观察到前角神经元有轻度神经元丢失。近端轴突中的空泡样改变更明显，包括轴突肿胀（球状体）和前角神经毡。轴突中的空泡常常大到足以占据几乎整个轴突管径。前根出现退行性变，表现为空泡样改变和髓鞘卵圆体。在包括肿胀轴突（球状体）的神经元突起中，经常可见由比NFs更粗的细丝组成的路易体样包涵体（LIs）（直径约大1.5倍），偶尔在胞体中也可见到。在32周（症状期），前角出现中度至重度神经元丢失，并伴有明显的星形胶质细胞增生。在前角经常观察到由积累的NFs组成的索状肿胀轴突和许多神经丝聚集。前角神经毡和前根中的空泡样改变不太明显或消失，而在包括索状肿胀轴突在内的神经元突起中经常可见LIs。在前根中，明显的纤维丢失和频繁的髓鞘卵圆体等退行性改变很显著。在任何阶段，胞体或近端树突中均未检测到NFs的积累或线粒体空泡化。这些发现表明，在该转基因小鼠模型中，近端轴突的轴突运输慢速成分在早期就受到损害，这种损害可能是由于NFs的机械阻碍，或者是由于轴突流最初因空泡样改变而受阻，随后因LIs的积累而加剧，导致NFs在近端轴突中积累所致。
