Cryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates

Commun Biol. 2021 Jul 8;4(1):849. doi: 10.1038/s42003-021-02360-2.


Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine (polyQ) tract in the mutant huntingtin (mHTT) protein. The formation and topology of filamentous mHTT inclusions in the brain (hallmarks of HD implicated in neurotoxicity) remain elusive. Using cryo-electron tomography and subtomogram averaging, here we show that mHTT exon 1 and polyQ-only aggregates in vitro are structurally heterogenous and filamentous, similar to prior observations with other methods. Yet, we find filaments in both types of aggregates under ~2 nm in width, thinner than previously reported, and regions forming large sheets. In addition, our data show a prevalent subpopulation of filaments exhibiting a lumpy slab morphology in both aggregates, supportive of the polyQ core model. This provides a basis for future cryoET studies of various aggregated mHTT and polyQ constructs to improve their structure-based modeling as well as their identification in cells without fusion tags.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Electron Microscope Tomography / methods*
  • Exons / genetics*
  • Humans
  • Huntingtin Protein / chemistry
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / ultrastructure
  • Huntington Disease / genetics
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / ultrastructure
  • Mutation*
  • Peptides / genetics*
  • Protein Aggregates
  • Protein Aggregation, Pathological
  • Protein Conformation


  • HTT protein, human
  • Huntingtin Protein
  • Mutant Proteins
  • Peptides
  • Protein Aggregates
  • polyglutamine