A Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation

Mol Cell. 2018 May 17;70(4):588-601.e6. doi: 10.1016/j.molcel.2018.04.007. Epub 2018 May 10.


Huntington's disease is caused by an abnormally long polyglutamine tract in the huntingtin protein. This leads to the generation and deposition of N-terminal exon1 fragments of the protein in intracellular aggregates. We combined electron tomography and quantitative fluorescence microscopy to analyze the structural and material properties of huntingtin exon1 assemblies in mammalian cells, in yeast, and in vitro. We found that huntingtin exon1 proteins can form reversible liquid-like assemblies, a process driven by huntingtin's polyQ tract and proline-rich region. In cells and in vitro, the liquid-like assemblies converted to solid-like assemblies with a fibrillar structure. Intracellular phase transitions of polyglutamine proteins could play a role in initiating irreversible pathological aggregation.

Keywords: aggregation; electron tomography; fluorescence microscopy; huntingtin exon1; phase transition; polyQ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exons
  • HEK293 Cells
  • Humans
  • Huntingtin Protein / chemistry*
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology*
  • Peptides / chemistry*
  • Peptides / genetics
  • Phase Transition*
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology*
  • Saccharomyces cerevisiae


  • Huntingtin Protein
  • Peptides
  • polyglutamine