Formation and removal of α-synuclein aggregates in cells exposed to mitochondrial inhibitors
Formation and removal of α-synuclein aggregates in cells exposed to mitochondrial inhibitors
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DOI：
10.1074/jbc.m105326200
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发表时间：
2002-02-15
影响因子：
4.8
通讯作者：
Lee, SJ
中科院分区：
文献类型：
--
作者：
Lee, HJ;Shin, SY;Lee, SJ
线粒体功能障碍与帕金森病有关。然而，线粒体缺陷在路易小体（帕金森病的病理标志）形成中的作用尚未得到直接解决。在本报告中，我们研究了线粒体电子传递链抑制剂对路易小体主要蛋白质成分-突触核蛋白聚集的影响。用鱼藤酮（一种复合物I的抑制剂）处理导致抗洗涤剂α -突触核蛋白聚集体的增加和ATP水平的降低。另一种电子传递链抑制剂寡霉素也显示了聚集体形成与ATP还原之间的时间相关性。显微分析显示，α -突触核蛋白的小聚集体逐渐演变成一个大的核周包涵体。包涵体与泛素、20s蛋白酶体、γ -微管蛋白和波形蛋白共染色。核周包涵体呈硫黄素s阳性，而小的细胞质聚集体不呈硫黄素s阳性，提示淀粉样构象。有趣的是，当细胞补充无抑制剂的培养基时，聚集体消失。聚集体的消失与线粒体代谢的恢复一致，并被蛋白酶体抑制剂部分抑制。这些结果表明，α -突触核蛋白包涵体的形成可能由线粒体功能受损引发，并通过恢复正常的线粒体代谢来逆转。
Mitochondrial dysfunction has been associated with Parkinson's disease. However, the role of mitochondrial defects in the formation of Lewy bodies, a pathological hallmark of Parkinson's disease has not been addressed directly. In this report, we investigated the effects of inhibitors of the mitochondria) electron-transport chain on the aggregation of alpha-synuclein, a major protein component of Lewy bodies. Treatment with rotenone, an inhibitor of complex I, resulted in an increase of detergent-resistant alpha-synuclein aggregates and a reduction in ATP level. Another inhibitor of the electron-transport chain, oligomycin, also showed temporal correlation between the formation of aggregates and ATP reduction. Microscopic analyses showed a progressive evolution of small aggregates of alpha-synuclein to a large perinuclear inclusion body. The inclusions were co-stained with ubiquitin, 20 S proteasome, gamma-tubulin, and vimentin. The perinuclear inclusion bodies, but not the small cytoplasmic aggregates, were thioflavin S-positive, suggesting the amyloid-like conformation. Interestingly, the aggregates disappeared when the cells were replenished with inhibitor-free medium. Disappearance of aggregates coincided with the recovery of mitochondrial metabolism and was partially inhibited by proteasome inhibitors. These results suggest that the formation of alpha-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metabolism.