Excitotoxin-induced caspase-3 activation and microtubule disintegration in axons is inhibited by taxol.
Excitotoxin-induced caspase-3 activation and microtubule disintegration in axons is inhibited by taxol.
复制标题
DOI：
10.1186/2051-5960-1-59
复制
发表时间：
2013-09-09
影响因子：
7.1
通讯作者：
Vickers JC
中科院分区：
文献类型：
--
作者：
King AE;Southam KA;Dittmann J;Vickers JC
轴突变性是许多神经退行性疾病和损伤的关键病理事件，可由体树突兴奋性毒素引起。然而，目前尚不清楚兴奋性毒素诱导的轴突变性是否在机制上类似于轴突横断后发生的沃勒变性，但不涉及轴突半胱天冬酶激活。我们使用小鼠原代皮层神经元在体外培养9天，在隔室培养模型，允许分离的轴突从索马，检查兴奋性毒素诱导的轴突变性的病理级联。慢性暴露于红藻氨酸诱导的兴奋性毒性导致轴突断裂，这与轴突隔室中的半胱天冬酶-3的激活有关。为了研究微管在这些事件中的作用，微管稳定剂紫杉醇被添加到轴突或体树突隔室。我们的研究结果表明，微管稳定的轴突导致在一个显着减少的数量碎片轴突兴奋毒素暴露后。有趣的是，紫杉醇暴露于体树突或轴突隔室导致轴突中caspase-3活化减少，表明caspase活化是微管不稳定的下游事件，涉及来自细胞索马的信号传导。这些数据表明，兴奋性毒素诱导的轴突变性显示出一些沃勒变性的机制差异，微管稳定可能有助于保护神经细胞免受兴奋性毒性作用。
Axon degeneration, a key pathological event in many neurodegenerative diseases and injury, can be induced by somatodendritic excitotoxin exposure. It is currently unclear, however, whether excitotoxin-induced axon degeneration is mechanistically similar to Wallerian degeneration, which occurs following axon transection, but does not involve axonal caspase activation. We have used mouse primary cortical neurons at 9 days in vitro, in a compartmented culture model that allows separation of the axon from the soma, to examine the pathological cascade of excitotoxin-induced axon degeneration. Excitotoxicity induced by chronic exposure to kainic acid, resulted in axonal fragmentation, which was associated with activation of caspase-3 in the axonal compartment. To examine the role of microtubules in these events, the microtubule-stabilizing agent, taxol, was added to either the axonal or somatodendritic compartment. Our results demonstrated that microtubule stabilization of axons resulted in a significant reduction in the number of fragmented axons following excitotoxin exposure. Interestingly, taxol exposure to either the somatodendritic or axonal compartment resulted in reduced caspase-3 activation in axons, suggesting that caspase activation is a downstream event of microtubule destabilization and involves signalling from the cell soma. These data suggest that excitotoxin-induced axon degeneration shows some mechanistic differences to Wallerian degeneration, and that microtubule stabilization may assist in protecting nerve cells from excitotoxic effects.
登录
查看更多内容
影响因子：
9.2
作者：
Ferri, A;Sanes, JR;Kato, AC
通讯作者：
Kato, AC
影响因子：
25
作者：
Mack, TGA;Reiner, M;Coleman, MP
通讯作者：
Coleman, MP
影响因子：
3.4
作者：
LUNN, ER;PERRY, VH;GORDON, S
通讯作者：
GORDON, S
影响因子：
5.3
作者：
Hoskison, M. M.;Shuttleworth, C. William
通讯作者：
Shuttleworth, C. William
影响因子：
5.3
作者：
Chen, Mark;Maloney, Janice A.;Watts, Ryan J.
通讯作者：
Watts, Ryan J.