Sahenk Z, Mendell J R
Norman Allen Department of Neurology, Ohio State University, Columbus 43210.
J Neurosci Res. 1992 Aug;32(4):481-93. doi: 10.1002/jnr.490320404.
Estramustine phosphate (EP) disassembles microtubules by binding to microtubule-associated proteins (MAPs) rather than tubulin. In this study, EP-induced alterations of MAP integrity caused a unique form of axonal atrophy in rats. Initially, EP-induced axonal atrophy occurred in both proximal and distal axons of the sciatic nerve, characterized by an increase in neurofilament packing density, associated with a decrease in axonal area. In chronic exposure, distal axonal atrophy was associated with decreased numbers of microtubules, while the neurofilament number remained unaltered for the myelin spiral length. Continued exposure caused enlargement of proximal axons associated with an increase in neurofilament content. Correlative slow transport studies done at two different times, 7 and 14 days after [35S] methionine injection showed that EP retards the transport of cytoskeletal proteins migrating with both components of slow transport (SCa and SCb). However, there was a differential effect on SCb which showed progressive slowing along the nerve while the rate of SCa stayed relatively constant. In this model, the early occurring distal axonal atrophy can best be explained by reduced cytoskeletal components, particularly those traveling in SCb. Later in the course of intoxication, a relatively constant rate of SCa permitted continuous transport of neurofilament triplets, accounting for unaltered numbers of neurofilaments in distal axons with increased packing density. This model of axonal atrophy is unique because spacing of neurofilaments, not numbers determined axon size. Furthermore, EP-induced dissociation of the SCa and SCb kinetics suggests that MAPs play a role in the orderly, cohesive migration of slow transport components, essential for the normal organization of cytoskeleton.
磷酸雌莫司汀（EP）通过与微管相关蛋白（MAPs）而非微管蛋白结合来拆解微管。在本研究中，EP诱导的MAP完整性改变在大鼠中导致了一种独特形式的轴突萎缩。最初，EP诱导的轴突萎缩发生在坐骨神经的近端和远端轴突，其特征是神经丝堆积密度增加，同时轴突面积减小。在慢性暴露中，远端轴突萎缩与微管数量减少相关，而在髓鞘螺旋长度范围内神经丝数量保持不变。持续暴露导致近端轴突增大，同时神经丝含量增加。在[35S]甲硫氨酸注射后7天和14天这两个不同时间进行的相关慢速运输研究表明，EP会延缓与慢速运输的两个组分（SCa和SCb）一起迁移的细胞骨架蛋白的运输。然而，对SCb有不同的影响，SCb沿神经显示出逐渐减慢，而SCa的速率保持相对恒定。在这个模型中，早期发生的远端轴突萎缩最好用细胞骨架组分减少来解释，特别是那些通过SCb运输的组分。在中毒过程后期，SCa相对恒定的速率允许神经丝三联体持续运输，这解释了远端轴突中神经丝数量不变但堆积密度增加的现象。这种轴突萎缩模型是独特的，因为神经丝的间距而非数量决定轴突大小。此外，EP诱导的SCa和SCb动力学解离表明，MAPs在慢速运输组分的有序、连贯迁移中起作用，这对细胞骨架的正常组织至关重要。
