In Situ Architecture and Cellular Interactions of PolyQ Inclusions
In Situ Architecture and Cellular Interactions of PolyQ Inclusions
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DOI：
10.1016/j.cell.2017.08.009
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发表时间：
2017-09-21
期刊：
影响因子：
64.5
通讯作者：
Fernandez-Busnadiego, Ruben
中科院分区：
文献类型：
--
作者：
Baeuerlein, Felix J. B.;Saha, Itika;Fernandez-Busnadiego, Ruben
许多疾病相关的聚集蛋白的表达会导致细胞毒性和大的细胞内包涵体的形成。为了深入了解包涵体在病理学中的作用和细胞内蛋白质聚集体的原位结构，我们使用先进的冷冻电子断层扫描方法分析了多谷氨酰胺(PolyQ)-亨廷顿蛋白外显子1在其完整的细胞环境中形成的包涵体的结构。在原代小鼠神经元和永生化的人类细胞中，多聚Q包涵体由淀粉样纤维组成，与细胞内膜相互作用，特别是内质网(ER)。与这些纤维的相互作用导致膜变形，内质网组织局部受损，包涵体周围的内质网膜动力学发生深刻变化。这些结果表明，纤维和内膜之间的异常相互作用导致了蛋白质聚集的有害细胞效应。
Expression of many disease-related aggregationprone proteins results in cytotoxicity and the formation of large intracellular inclusion bodies. To gain insight into the role of inclusions in pathology and the in situ structure of protein aggregates inside cells, we employ advanced cryo-electron tomography methods to analyze the structure of inclusions formed by polyglutamine (polyQ)-expanded huntingtin exon 1 within their intact cellular context. In primary mouse neurons and immortalized human cells, polyQ inclusions consist of amyloid-like fibrils that interact with cellular endomembranes, particularly of the endoplasmic reticulum (ER). Interactions with these fibrils lead to membrane deformation, the local impairment of ER organization, and profound alterations in ER membrane dynamics at the inclusion periphery. These results suggest that aberrant interactions between fibrils and endomembranes contribute to the deleterious cellular effects of protein aggregation.