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.

中文翻译：

---

PolyQ夹杂物的原位架构和细胞相互作用。

许多与疾病相关的易于聚集的蛋白的表达导致细胞毒性和大的细胞内包涵体的形成。为了深入了解内含物在病理学中的作用以及细胞内蛋白质聚集体的原位结构，我们采用了先进的低温电子断层扫描方法来分析由聚谷氨酰胺（polyQ）扩展的亨廷顿外显子1在其完整细胞内形成的内含物的结构。语境。在原代小鼠神经元和永生化的人类细胞中，polyQ夹杂物由与细胞内膜，特别是内质网（ER）相互作用的淀粉样蛋白样原纤维组成。与这些原纤维的相互作用导致膜变形，内质网组织的局部损伤以及内含物周边内质网膜动力学的深刻变化。这些结果表明，原纤维和内膜之间的异常相互作用促进了蛋白质聚集的有害细胞作用。视频摘要。