Effect of Taxoid and Nontaxoid Site Microtubule-Stabilizing Agents on Axonal Transport of Mitochondria in Untransfected and ECFP-htau40-Transfected Rat Cortical Neurons in Culture
Effect of Taxoid and Nontaxoid Site Microtubule-Stabilizing Agents on Axonal Transport of Mitochondria in Untransfected and ECFP-htau40-Transfected Rat Cortical Neurons in Culture
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DOI：
10.1002/jnr.23394
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发表时间：
2014-09-01
影响因子：
4.2
通讯作者：
Miller, John H.
中科院分区：
文献类型：
--
作者：
Das, Viswanath;Sim, Dalice A.;Miller, John H.
脑中突触可塑性的一个重要方面是必需成分如线粒体从索马到突触的轴突运输。为了不间断地将细胞货物运输到轴突，需要功能性微管。微管相关tau蛋白表达的变化引起的微管动力学改变影响正常微管功能并干扰轴突运输。在这里，我们调查的非紫杉醇结合位点微管稳定剂peloruside A（PelA）和laulimalide的影响，与紫杉醇位点结合剂紫杉醇（Ptx）和伊沙匹隆相比，轴突运输线粒体在1天大的大鼠大脑皮层神经元培养。在过量tau表达的条件下，具体比较了这两种类型的化合物对线粒体运输的影响的差异。与Ptx和伊沙匹隆相比，PelA和laulimalide本身对线粒体转运没有不良影响，Ptx和伊沙匹隆在较高浓度下抑制线粒体游程长度。与Ptx一样，PelA能够部分逆转在ECFP-htau 40过表达神经元中观察到的线粒体转运受阻，尽管在较高浓度的微管稳定剂下，PelA反应优于Ptx反应。这些结果支持微管稳定在维持过度表达tau蛋白的神经元中的轴突运输中的神经保护作用，并且可能有益于降低神经退行性疾病如阿尔茨海默病的严重程度。(C)2014 Wiley Periodicals，Inc.
An important aspect of synaptic plasticity in the brain is axonal transport of essential components such as mitochondria from the soma to the synapse. For uninterrupted transport of cellular cargo down the axon, functional microtubules are required. Altered microtubule dynamics induced by changes in expression of microtubule-associated tau protein affects normal microtubule function and interferes with axonal transport. Here we investigate the effects of the nontaxoid-binding-site microtubule-stabilizing agents peloruside A (PelA) and laulimalide, compared with the taxoid-site-binding agents paclitaxel (Ptx) and ixabepilone, on axonal transport of mitochondria in 1-day-old rat pup cerebral cortical neuron cultures. The differences in effects of these two types of compound on mitochondrial trafficking were specifically compared under conditions of excess tau expression. PelA and laulimalide had no adverse effects on their own on mitochondrial transport compared with Ptx and ixabepilone, which inhibited mitochondrial run length at higher concentrations. PelA, like Ptx, was able to partially reverse the blocked mitochondrial transport seen in ECFP-htau40-overexpressing neurons, although at higher concentrations of microtubule-stabilizing agent, the PelA response was improved over the Ptx response. These results support a neuroprotective effect of microtubule stabilization in maintaining axonal transport in neurons overexpressing tau protein and may be beneficial in reducing the severity of neurodegenerative diseases such as Alzheimer's disease. (C) 2014 Wiley Periodicals, Inc.