Sahenk Z, Chen L, Mendell J R
Department of Neurology, Neuromuscular Disease Center, College of Medicine, Ohio State University, Columbus 43210, USA.
Ann Neurol. 1999 Jan;45(1):16-24. doi: 10.1002/1531-8249(199901)45:1<16::aid-art5>3.0.co;2-f.
Axonal loss in Charcot-Marie-Tooth type 1A (CMT1A) is an important feature correlated with the functional disability in affected individuals. It is not known, however, how the most common genetic defect in Schwann cells (PMP22 duplication) causes the CMT1A phenotype and results in axonal loss. In this study, sural nerve segments from individuals with PMP22 duplications or deletions, causing the reciprocal disorder hereditary neuropathy with pressure palsies (HNPP), were grafted into the cut ends of the sciatic nerve of nude mice. The xenografts and host segments were studied at 2, 4, 6, 8, 12, and 16 weeks after grafting and compared with the controls from healthy volunteers. Within the CMT1A xenografts, the nude mice axons in the proximal part of the graft showed a significant increase in axonal area with an increase in the neurofilament and membranous organelle (mitochondria) density, compared with distal graft and distal host segments. A preferential distal axonal loss, associated with a perpetual axonal atrophy, degeneration, and axonal sprouting was observed over time, with increasing intensity at 8 to 16 weeks. These alterations were seen to a lesser extent in HNPP xenografts and were not observed in controls. In addition, the onset of regeneration-associated myelination was delayed, more significantly in HNPP xenografts than those of CMT1A. Our findings indicate that the PMP22 duplication in Schwann cells results in an impairment in the normal axonal cytoskeletal organization, resulting in distal axonal degeneration and fiber loss, and the affect of PMP22 deletion on axonal cytoskeleton is less deleterious.
1A型遗传性运动感觉神经病（CMT1A）中的轴突损失是与受影响个体功能残疾相关的一个重要特征。然而，尚不清楚施万细胞中最常见的基因缺陷（外周髓鞘蛋白22基因重复）如何导致CMT1A表型并导致轴突损失。在本研究中，将因外周髓鞘蛋白22基因重复或缺失导致互为相反疾病——遗传性压迫易感性神经病（HNPP）的个体的腓肠神经节段移植到裸鼠坐骨神经的切断端。在移植后2、4、6、8、12和16周对异种移植物和宿主节段进行研究，并与健康志愿者的对照进行比较。在CMT1A异种移植物中，与移植物远端和宿主远端节段相比，移植物近端的裸鼠轴突的轴突面积显著增加，神经丝和膜性细胞器（线粒体）密度增加。随着时间的推移，观察到轴突优先向远端损失，并伴有持续性轴突萎缩、变性和轴突发芽，在8至16周时强度增加。这些改变在HNPP异种移植物中程度较轻，在对照中未观察到。此外，与再生相关的髓鞘形成开始延迟，在HNPP异种移植物中比在CMT1A异种移植物中更显著。我们的研究结果表明，施万细胞中的外周髓鞘蛋白22基因重复导致正常轴突细胞骨架组织受损，导致远端轴突变性和纤维丢失，并且外周髓鞘蛋白22基因缺失对轴突细胞骨架的影响危害较小。
