Neuromelanin selectively induces apoptosis in dopaminergic SH‐SY5Y cells by deglutathionylation in mitochondria: involvement of the protein and melanin component
Neuromelanin selectively induces apoptosis in dopaminergic SH‐SY5Y cells by deglutathionylation in mitochondria: involvement of the protein and melanin component
复制标题
神经黑色素通过线粒体中的去谷胱甘肽选择性诱导多巴胺能 SH-SY5Y 细胞凋亡：蛋白质和黑色素成分的参与
DOI：
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发表时间：
2008
影响因子：
4.7
通讯作者：
P. Riederer
中科院分区：
文献类型：
--
作者：
M. Naoi;W. Maruyama;H. Yi;Y. Yamaoka;M. Shamoto‐Nagai;Y. Akao;M. Gerlach;Masashi Tanaka;P. Riederer
帕金森病 (PD) 的特征是含有神经黑色素 (NM) 的黑质多巴胺 (DA) 神经元的选择性耗竭，表明 NM 参与了发病机制。这项研究报告了 NM 在 SH-SY5Y 细胞中诱导细胞凋亡，而蛋白酶 K 处理的 NM、合成的 DA 和半胱氨酰多巴胺黑色素显示出细胞毒性要小得多。细胞死亡是由线粒体介导的凋亡途径介导的，即线粒体膜电位的崩溃、细胞色素c的释放和caspase 3的激活，但Bcl-2的过度表达并不能抑制细胞凋亡。 NM增加了线粒体中的硫氢基含量，其中大部分被鉴定为GSH，而多巴胺黑色素则显着降低了硫氢基水平。蛋白质结合 GSH 的蛋白质印迹分析表明，只有 NM 才能减少线粒体中的 S-谷胱甘肽化蛋白，并解离复合物 I 的大分子结构。NM 的去谷胱甘肽化需要活性氧和氮物质，抗氧化剂显着减少，从而防止细胞凋亡。这些结果表明，NM 可能通过调节线粒体氧化还原状态和 S-谷胱甘肽与 PD 中 DA 神经元的细胞死亡和衰老有关，而 NM 相关蛋白是绝对需要的。讨论了 NM 的新功能与 PD 发病机制的关系。
Parkinson’s disease (PD) is characterized by selective depletion of nigral dopamine (DA) neurons containing neuromelanin (NM), suggesting the involvement of NM in the pathogenesis. This study reports induction of apoptosis by NM in SH‐SY5Y cells, whereas protease‐K‐treated NM, synthesized DA‐ and cysteinyl dopamine melanin showed much less cytotoxicity. Cell death was mediated by mitochondria‐mediated apoptotic pathway, namely collapse of mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3, but Bcl‐2 over‐expression did not suppress apoptosis. NM increased sulfhydryl content in mitochondria, and a major part of it was identified as GSH, whereas dopamine melanin significantly reduced sulfhydryl levels. Western blot analysis for protein‐bound GSH demonstrated that only NM reduced S‐glutathionylated proteins in mitochondria and dissociated macromolecular structure of complex I. Reactive oxygen and nitrogen species were required for the deglutathionylation by NM, which antioxidants reduced significantly with prevention of apoptosis. These results suggest that NM may be related to cell death of DA neurons in PD and aging through regulation of mitochondrial redox state and S‐glutathionylation, for which NM‐associated protein is absolutely required. The novel function of NM is discussed in relation to the pathogenesis of PD.
影响因子：
56.9
作者：
DAMATO, RJ;LIPMAN, ZP;SNYDER, SH
通讯作者：
SNYDER, SH
DOI：
10.1016/0925-4439(95)00007-q
发表时间：
1995-05-24
影响因子：
6.2
作者：
MEISTER, A
通讯作者：
MEISTER, A