...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasis
【24h】

The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasis

机译：帕金森氏病蛋白α-突触核蛋白破坏细胞Rab稳态

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

α-Synuclein (α-syn), a protein of unknown function, is the most abundant protein in Lewy bodies, the histological hallmark of Parkinson's disease (PD). In yeast α-syn inhibits endoplasmic retic-ulum (ER)-to-Golgi (ER→Golgi) vesicle trafficking, which is rescued by overexpression of a Rab GTPase that regulates ER→Golgi trafficking. The homologous Rab1 rescues α-syn toxicity in dopa-minergic neuronal models of PD. Here we investigate this conserved feature of α-syn pathobiology. In a cell-free system with purified transport factors α-syn inhibited ER→Golgi trafficking in an α-syn dose-dependent manner. Vesicles budded efficiently from the ER, but their docking or fusion to Golgi membranes was inhibited. Thus, the in vivo trafficking problem is due to a direct effect of α-syn on the transport machinery. By ultrastructural analysis the earliest in vivo defect was an accumulation of morphologically undocked vesicles, starting near the plasma membrane and growing into massive intracellular vesicular clusters in a dose-dependent manner. By immunofluorescence/immunoelec-tron microscopy, these clusters were associated both with α-syn and with diverse vesicle markers, suggesting that α-syn can impair multiple trafficking steps. Other Rabs did not ameliorate α-syn toxicity in yeast, but RAB3A, which is highly expressed in neurons and localized to presynaptic termini, and RAB8A, which is localized to post-Golgi vesicles, suppressed toxicity in neuronal models of PD. Thus, α-syn causes general defects in vesicle trafficking, to which dopaminergic neurons are especially sensitive.
机译：α-突触核蛋白（α-syn）是一种功能未知的蛋白质，是路易体中含量最高的蛋白质，这是帕金森氏病（PD）的组织学标志。在酵母中，α-syn抑制内质网（ER）向高尔基体（ER→高尔基体）的囊泡运输，这可以通过调节ER→高尔基体运输的Rab GTPase的过量表达来挽救。同源的Rab1在PD多巴能神经元模型中挽救了α-syn毒性。在这里，我们研究了α-syn病理生物学的这一保守特征。在具有纯化转运因子的无细胞系统中，α-syn以剂量依赖性方式抑制ER→高尔基体运输。囊泡从内质网有效萌芽，但它们对接或融合到高尔基体膜受到抑制。因此，体内运输问题是由于α-syn对运输机械的直接作用。通过超微结构分析，最早的体内缺陷是形态上未对接的囊泡的积累，开始于质膜附近，并以剂量​​依赖的方式生长成大量的细胞内囊泡簇。通过免疫荧光/免疫电镜观察，这些簇与α-syn和多种囊泡标志物相关，表明α-syn可以损害多个运输步骤。其他Rabs并未改善酵母中的α-syn毒性，但是在神经元中高表达并定位在突触前末端的RAB3A和在高尔基体后囊泡定位的RAB8A抑制了PD神经元模型的毒性。因此，α-syn引起囊泡运输中的一般缺陷，多巴胺能神经元对此特别敏感。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号