Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo

Cell. 1997 Aug 8;90(3):549-58. doi: 10.1016/s0092-8674(00)80514-0.


The mechanism by which an elongated polyglutamine sequence causes neurodegeneration in Huntington's disease (HD) is unknown. In this study, we show that the proteolytic cleavage of a GST-huntingtin fusion protein leads to the formation of insoluble high molecular weight protein aggregates only when the polyglutamine expansion is in the pathogenic range. Electron micrographs of these aggregates revealed a fibrillar or ribbon-like morphology, reminiscent of scrapie prions and beta-amyloid fibrils in Alzheimer's disease. Subcellular fractionation and ultrastructural techniques showed the in vivo presence of these structures in the brains of mice transgenic for the HD mutation. Our in vitro model will aid in an eventual understanding of the molecular pathology of HD and the development of preventative strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid
  • Animals
  • Base Sequence
  • Brain / pathology
  • Cell Nucleus / pathology
  • DNA Primers
  • Exons
  • Glutathione Transferase
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Kidney / pathology
  • Macromolecular Substances
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics*
  • Polymerase Chain Reaction
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / chemistry


  • Amyloid
  • DNA Primers
  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Macromolecular Substances
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Glutathione Transferase