Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Cell. 2017 Sep 21;171(1):179-187.e10. doi: 10.1016/j.cell.2017.08.009. Epub 2017 Sep 7.
Expression of many disease-related aggregation-prone 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. VIDEO ABSTRACT.
许多与疾病相关的易于聚集的蛋白质的表达会导致细胞毒性和大的细胞内包含体的形成。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物的原位结构，我们采用先进的冷冻电子断层成像方法来分析聚谷氨酰胺（polyQ）扩展的 huntingtin 外显子 1 在其完整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细胞中，polyQ 包涵体由类似淀粉样的纤维组成，这些纤维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、内质网组织的局部损伤以及包涵体周围 ER 膜动力学的深刻改变。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。视频摘要。
