Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease?
Is Bax a mitochondrial mediator in apoptotic death of dopaminergic neurons in Parkinson's disease?
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DOI：
10.1046/j.1471-4159.2001.00160.x
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发表时间：
2001-03-01
影响因子：
4.7
通讯作者：
Hirsch, EC
中科院分区：
文献类型：
--
作者：
Hartmann, A;Michel, PP;Hirsch, EC
Bax 是 Bcl-2 蛋白家族的促凋亡成员。人们认为它主要通过促进细胞色素c从线粒体膜间隙释放到胞质溶胶中来发挥其作用，从而导致半胱天冬酶激活和细胞死亡。由于在帕金森病患者的大脑中死后观察到线粒体呼吸功能、半胱天冬酶激活和细胞死亡的改变，其形态学特征与细胞凋亡相一致，因此我们试图在对正常和帕金森病死后大脑和经 MPP+ 处理的原代中脑细胞培养物进行免疫组织化学研究中阐明 Bax 在这一过程中的潜在作用。我们发现，在正常和帕金森病受试者死后大脑以及体外，多巴胺能 (DA) 神经元普遍表达 Bax。使用插入线粒体外膜的 Bax 抗体作为 Bax 激活的指标，无论分析的中脑亚区域如何，在对照受试者和帕金森病受试者之间均未观察到显着差异。然而，在帕金森病受试者中，含有路易体的 Bax 阳性黑化 SNpc 神经元（提示 DA 神经元遭受痛苦）的百分比显着高于黑化神经元中 Bax 阳性神经元的总体百分比。此外，帕金森病受试者中具有激活的 caspase-3 的所有黑色化 SNpc 神经元也对 Bax 具有免疫反应性，这表明锚定在黑色化 SNpc 神经元线粒体外膜上的 Bax 表现出神经元受损或细胞凋亡的迹象，与明显未改变的 DA 神经元相比。令人惊讶的是，原代中脑培养物中酪氨酸羟化酶（TH）阳性神经元的 MPP+ 处理并没有引起 Bax 的重新分布，尽管细胞色素 c 从线粒体中释放出来并诱导了核浓缩/断裂。总而言之，这些发现表明，在人类病理学中，Bax 可能是 caspase 激活的辅助因子，但我们的体外数据未能表明 Bax 在实验性帕金森病范例中的 DA 神经元凋亡中发挥核心作用。
Bax is a proapoptotic member of the Bcl-2 family of proteins. It is believed to exert its action primarily by facilitating the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, leading to caspase activation and cell death. Because alterations in mitochondrial respiratory function, caspase activation and cell death with morphologic features compatible with apoptosis have been observed post mortem in the brain of patients with Parkinson's disease, we tried to clarify the potential role of Bax in this process in an immunohistochemical study on normal and Parkinson's disease post-mortem brain and primary mesencephalic cell cultures treated with MPP+. We found that Bax is expressed ubiquitously by dopaminergic (DA) neurons in postmortem brain of normal and Parkinson's disease subjects as well as in vitro. Using an antibody to Bax inserted into the outer mitochondrial membrane as an index of Bax activation, no significant differences were observed between control and Parkinson's disease subjects, regardless of the mesencephalic subregion analysed. However, in Parkinson's disease subjects, the percentage of Bax-positive melanized SNpc neurons containing Lewy bodies, suggestive of DA neuronal suffering, was significantly higher than the overall percentage of Bax-positive neurons among melanized neurons. Furthermore, all melanized SNpc neurons in Parkinson's disease subjects with activated caspase-3 were also immunoreactive for Bax, suggesting that Bax anchored in the outer mitochondrial membrane of melanized SNpc neurons showing signs of neuronal suffering or apoptosis is increased compared with DA neurons that are apparently unaltered. Surprisingly, MPP+ treatment of tyrosine hydroxylase (TH)-positive neurons in primary mesencephalic cultures did not cause redistribution of Bax, although cytochrome c was released from the mitochondria and nuclear condensation/fragmentation was induced. Taken together, these findings suggest that in the human pathology, Bax may be a cofactor in caspase activation, but our in vitro data fail to indicate a central role for Bax in apoptotic death of DA neurons in an experimental Parkinson's disease paradigm.