In Situ Architecture and Cellular Interactions of PolyQ Inclusions

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.

Keywords: amyloid fibril; cryo-EM; cryo-electron tomography; cryo-focused ion beam milling; endoplasmic reticulum; inclusion body; membrane disruption; polyglutamine expansion; protein aggregation.

MeSH terms

  • Amyloid / chemistry
  • Animals
  • Cryoelectron Microscopy
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Female
  • HeLa Cells
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / pathology*
  • Inclusion Bodies / chemistry
  • Inclusion Bodies / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Mutation
  • Neurons / pathology*
  • Neurons / ultrastructure*
  • Peptides / metabolism*
  • Protein Aggregation, Pathological
  • Tomography / methods


  • Amyloid
  • HTT protein, human
  • Huntingtin Protein
  • Peptides
  • polyglutamine