Mechanisms of Axonal Spheroid Formation in Central Nervous System Wallerian Degeneration
Mechanisms of Axonal Spheroid Formation in Central Nervous System Wallerian Degeneration
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DOI：
10.1097/nen.0b013e3181da84db
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发表时间：
2010-05-01
影响因子：
3.2
通讯作者：
Coleman, Michael P.
中科院分区：
文献类型：
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作者：
Beirowski, Bogdan;Nogradi, Antal;Coleman, Michael P.
中枢神经系统的沃勒变性伴有轴突营养不良或肿胀。为了了解severity产生的机制，我们研究了它们的时空动力学，超微结构，组成，以及影响它们在体内和体外形成的条件。与周围神经轴突相反，损伤的视神经（ON）轴突在体内在6小时内不同步地发展成局灶性硬化，远早于存在任何轴突断裂。ON、脊髓背柱和胼胝体中的轴突在损伤后早期在其远端残端的近端区域均显示出明显的梯度，并且具有更多的sediment。经验证的离体系统的延时成像显示，在接近损伤部位约1小时后出现多个局灶性脑脊髓炎，随后在连续ON轴突残端上出现顺行性波浪状进展。小行星在很大程度上是稳定的，但偶尔似乎会与相邻的小行星融合。它们的超微结构外观类似于疾病相关的球体。虽然轴突标志物的积累表明运输缺陷，线粒体的大量积累没有观察到。在表达Wld（S）基因的啮齿动物中，通过去除细胞外钙，早期肿胀形成减少。在体外和/或体内抑制轴突损失的几种药理学试剂也阻止了急性ON外植体中轴突球状体的早期形成。由于轴突肿胀是许多神经退行性疾病的标志，这些数据表明，在某些情况下，它们是沃勒样变性的表现。因此，Wallerian样变性可能是CNS疾病中比以前认为的更常见的组成机制。
Wallerian degeneration of the CNS is accompanied by axonal dystrophy or swelling. To understand the mechanisms by which swellings arise, we studied their spatiotemporal dynamics, ultrastructure, composition, and the conditions that affect their formation in vivo and ex vivo. In contrast to peripheral nerve axons, lesioned optic nerve (ON) axons in vivo developed focal swellings asynchronously within 6 hours, long before there is any axon fragmentation. Axons in ON, spinal cord dorsal column, and corpus callosum all showed marked gradients with more swellings in proximal regions of their distal stumps early after lesion. Time-lapse imaging of a validated ex vivo system showed that multiple focal swellings arise after around 1 hour close to the injury site, followed by anterograde wave-like progression on continuous ON axon stumps. Swellings were largely stable but occasionally seemed to fuse with neighboring swellings. Their ultrastructural appearances resembled disease-associated spheroids. Although accumulation of axonal markers suggested transport deficits, large accumulations of mitochondria were not observed. Early swelling formation was decreased in Wld(S) gene-expressing rodents and by removing extracellular calcium. Several pharmacologic agents that inhibit axon loss in vitro and/or in vivo also prevented early formation of axonal spheroids in acute ON explants. Because axonal swellings are hallmarks of many neurodegenerative conditions, these data suggest that they are a manifestation of Wallerian-like degeneration in some cases. Thus, Wallerian-like degeneration may be a more common component mechanism in CNS diseases than previously thought.