Selective vulnerability of dopaminergic neurons to microtubule depolymerization
Selective vulnerability of dopaminergic neurons to microtubule depolymerization
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DOI：
10.1074/jbc.m503483200
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发表时间：
2005-10-07
影响因子：
4.8
通讯作者：
Feng, J
中科院分区：
文献类型：
--
作者：
Ren, Y;Liu, WH;Feng, J
帕金森病（Parkinson disease，PD）是一种以黑质多巴胺能（dopaminergic，DA）神经元特异性变性为特征的疾病，与多种环境和遗传因素有关。鱼藤酮，一种环境PD毒素，表现出更大的毒性DA神经元在中脑神经元培养比非DA神经元。微管稳定药物紫杉醇可显著降低这种效应，而微管解聚剂如秋水仙碱或诺考达唑则可模拟这种效应。微管解聚破坏了沿着微管的囊泡运输，并导致多巴胺囊泡在索马中的积累。这导致由于从囊泡泄漏的胞质多巴胺的氧化而增加的氧化应激。多巴胺代谢的抑制显着降低鱼藤酮毒性。因此，我们的研究结果表明，微管解聚诱导的PD毒素，如鱼藤酮在多巴胺能神经元的选择性死亡中起着关键作用。
Parkinson disease (PD) is characterized by the specific degeneration of dopaminergic (DA) neurons in substantia nigra and has been linked to a variety of environmental and genetic factors. Rotenone, an environmental PD toxin, exhibited much greater toxicity to DA neurons in midbrain neuronal cultures than to non-DA neurons. The effect was significantly decreased by the microtubule-stabilizing drug taxol and mimicked by microtubule-depolymerizing agents such as colchicine or nocodazole. Microtubule depolymerization disrupted vesicular transport along microtubules and caused the accumulation of dopamine vesicles in the soma. This led to increased oxidative stress due to oxidation of cytosolic dopamine leaked from vesicles. Inhibition of dopamine metabolism significantly reduced rotenone toxicity. Thus, our results suggest that microtubule depolymerization induced by PD toxins such as rotenone plays a key role in the selective death of dopaminergic neurons.