Programmed Axon Death, Synaptic Dysfunction and the Ubiquitin Proteasome System
Programmed Axon Death, Synaptic Dysfunction and the Ubiquitin Proteasome System
复制标题
DOI：
10.2174/1568007043337436
复制
发表时间：
2004-01-01
影响因子：
3
通讯作者：
Ribchester, R. R.
中科院分区：
文献类型：
--
作者：
Coleman, M. P.;Ribchester, R. R.
轴突至关重要、脆弱且往往不可替代，因此了解轴突如何在神经退行性疾病中丢失至关重要。最近的数据将损伤引起的沃勒变性机制与 CNS 和 PNS 疾病中的轴突死亡机制联系起来。神经保护基因 WldS 可以延缓华勒变性、中枢神经系统轴突营养不良、“死亡”病理，并在较小程度上延缓突触损失，尽管变性的原因和形态不同。这些发现验证了沃勒变性作为理解和预防神经退行性疾病中轴突和突触丢失机制的模型。改变沃勒变性的基因的存在表明它是轴突死亡的调节程序，通常由轴突抑制剂抑制，原则上与细胞凋亡相似。 WldS 蛋白和蛋白酶体抑制剂实验表明泛素蛋白酶体系统 (UPS) 与沃勒变性有关。然而，UPS 参与的部位和分子事件仍不清楚，因为 UPS 在神经元中高度分化，影响细胞核、轴突、生长锥和突触中复杂且有时相互冲突的过程。蛋白酶体抑制剂是研究如此复杂系统的钝器，它们对轴突具有特别的毒性并改变突触功能。相比之下，WldS 作用于特定步骤，使小鼠保持健康并具有正常的发育和行为。这也使其成为有吸引力的药物靶点。我们需要了解哪个 UPS 步骤在哪个神经元室中被阻断，并定义路径，以便开发新的策略来阻断轴突病理学。
Axons are essential, vulnerable and often irreplaceable so it is essential to understand how they are lost in neurodegenerative disease. Recent data link the mechanism of injury-induced Wallerian degeneration to that of axon death in CNS and PNS disease. The neuroprotective gene WldS delays Wallerian degeneration, CNS axonal dystrophy, 'dying-back' pathology and to a lesser extent synapse loss, despite the different causes and morphologies of degeneration. These findings validate Wallerian degeneration as a model to understand and prevent mechanisms of axon and synapse loss in neurodegenerative disorders.The existence of a gene that alters Wallerian degeneration suggests it is a regulated program of axon death normally held back by axonal inhibitors, similar in principle to apoptosis. The WldS protein and proteasome inhibitor experiments implicate the ubiquitin proteasome system (UPS) in Wallerian degeneration. However, the site of UPS involvement and the molecular events remain unclear because the UPS is highly compartmentalized in neurons, affecting complex and sometimes conflicting processes in nuclei, axons, growth cones and synapses. Proteasome inhibitors are blunt tools for studying such a complex system and they are also particularly toxic to axons and alter synapse function. In contrast, WldS acts on a specific step, leaving mice healthy with normal development and behavior. This also makes it an attractive drug target. We need to understand which UPS step is blocked in which neuronal compartment, and to define the pathway in order to develop new strategies to block axon pathology.