Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members
Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members
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DOI：
10.1111/j.1471-4159.2008.05293.x
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
Ethell, Douglas W.
中科院分区：
文献类型：
--
作者：
Fei, Qingyan;Ethell, Douglas W.
帕金森病的一个重要特征是黑质致密部多巴胺能神经元的变性。百草枯 (PQ) 和 MPTP 会导致体内这些神经元的选择性变性，而 PQ 与代森锰联合使用会加剧这种病理。阐明所涉及的细胞死亡机制对于了解多种环境毒素如何导致散发性帕金森病非常重要。我们最近报道，PQ 通过 Bak 激活诱导神经元凋亡，而 MPP+ 是 MPTP 的有毒代谢物，依赖于 Bax 和 p53。在这里，我们表明 PQ 和 Maneb 单独激活 Bak，但它们一起触发 Bax 依赖性细胞死亡。着眼于这种协同作用的机制，我们发现代森锰 + PQ 增加了三种强 Bak 抑制剂 Bfl-1、Bcl-xL 和 Mcl-1 的表达，并且还诱导了包括 Bik 和 Bim 在内的 Bax 激活剂。这些反应有利于 Bax 依赖性 MOMP 和细胞凋亡。 Bax 和 Bak 的 SiRNA 敲低证实，PQ 和代森锰单独诱导 Bak 依赖性细胞死亡，但它们一起阻断 Bak 途径并通过 Bax 激活细胞凋亡。
An important feature of Parkinson's disease is the degeneration of dopaminergic neurons in the Substantia Nigra pars compacta. Paraquat (PQ) and MPTP cause the selective degeneration of these neurons in vivo, and combining PQ with maneb exacerbates that pathology. Elucidation of the cell death mechanisms involved is important to understand how multiple environmental toxins may contribute to sporadic Parkinson's disease. We recently reported that PQ induces neuronal apoptosis through Bak activation, in contrast to MPP+, the toxic metabolite of MPTP, which relies on Bax and p53. Here we show that individually PQ and maneb activate Bak, but together they trigger Bax-dependent cell death. Focusing on mechanisms responsible for this synergy, we found that maneb+PQ increased the expression of three strong Bak inhibitors, Bfl-1, Bcl-xL and Mcl-1, and also induced Bax activators that included Bik and Bim. Those responses favor Bax-dependent MOMP and apoptosis. SiRNA knockdown of Bax and Bak confirmed that individually PQ and maneb induce Bak-dependent cell death, but together they block the Bak pathway and activate apoptosis through Bax.