Microtubule stabilization by peloruside A and paclitaxel rescues degenerating neurons from okadaic acid-induced tau phosphorylation
Microtubule stabilization by peloruside A and paclitaxel rescues degenerating neurons from okadaic acid-induced tau phosphorylation
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DOI：
10.1111/j.1460-9568.2012.08084.x
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发表时间：
2012-06-01
影响因子：
3.4
通讯作者：
Miller, John H.
中科院分区：
文献类型：
--
作者：
Das, Viswanath;Miller, John H.
许多细胞器必须在神经元中长距离运输以执行其特定功能，并且这种运输高度依赖于轴突内的微管网络。微管相关tau蛋白的过度磷酸化使微管不稳定并导致神经元细胞死亡。这种不稳定性可以通过使用微管稳定药物（如紫杉醇和埃博霉素）进行治疗来部分纠正。磷酸酶抑制剂冈田酸通过过度磷酸化tau蛋白来抑制神经元细胞培养物中神经突的生长。在这项研究中，使用来自出生后早期SpragueDawley大鼠大脑皮层的神经元培养物，我们研究了是否由peloruside A（一种微管稳定剂，与紫杉醇的β-微管蛋白上的不同位点结合）稳定微管，可以对抗暴露于15 nm冈田酸8 h的有害影响。Peloruside A逆转了在用冈田酸处理的神经元培养物中观察到的轴突生长和分支的减少，并从生长锥塌陷中拯救了神经元。虽然peloruside A对冈田酸引起的tau过度磷酸化没有影响，但它恢复了乙酰化微管蛋白（稳定微管的标志物）的水平，并逆转了冈田酸诱导的生长相关蛋白43（轴突生长调节剂）的抑制。因此，微管稳定药物显示出作为新的治疗剂用于治疗神经退行性疾病特征的受损微管网络的希望。
Many cellular organelles must travel long distances in neurons to perform their specific functions, and this transport is highly dependent on the microtubule network within the axon. Hyperphosphorylation of microtubule-associated tau protein destabilizes microtubules and leads to neuronal cell death. This destabilization can be corrected in part by treatment with microtubule-stabilizing drugs such as paclitaxel and epothilone. The phosphatase inhibitor okadaic acid inhibits the outgrowth of neurites in neuronal cell cultures by hyperphosphorylating tau protein. In this study using neuronal cultures derived from the cerebral cortex of early postnatal SpragueDawley rats, we examined whether stabilization of microtubules by peloruside A, a microtubule-stabilizing agent that binds to a different site on beta-tubulin from paclitaxel, could counter the deleterious effects of 8 h exposure to 15 nm okadaic acid. Peloruside A reversed the decrease in axonal outgrowth and branching seen in neuronal cultures treated with okadaic acid and rescued neurons from growth cone collapse. Although peloruside A had no effect on the hyperphosphorylation of tau caused by okadaic acid, it restored the levels of acetylated tubulin, a marker of stable microtubules, and reversed the okadaic acid-induced depression of growth-associated protein-43, an axonal growth regulator. Thus, microtubule-stabilizing drugs show promise as new therapeutic agents for treating damaged microtubule networks characteristic of neurodegenerative disease.