Structure of inclusions of Huntington's disease brain revealed by synchrotron infrared microspectroscopy: polymorphism and relevance to cytotoxicity

Anal Chem. 2013 Apr 2;85(7):3765-73. doi: 10.1021/ac400038b. Epub 2013 Mar 21.


Huntington's disease is caused by a polyglutamine expansion in huntingtin. Affected brain regions contain characteristic aggregates of the misfolded expanded protein. Studies in cells and animals show that aggregates are polymorphic and that the secondary structure of the aggregates is likely to condition their cytotoxicity. Therefore knowing the structure of aggregates is important as neurotoxic secondary structures may be specifically targeted during the search for prophylactic or therapeutic drugs. The structure of aggregates in the brain of patients is still unknown. Using synchrotron based infrared microspectroscopy we demonstrate that the brains of patients with Huntington disease contain putative oligomers and various kinds of microscopic aggregates (inclusions) that can be distinguished by their differential absorbance at 1627 cm(-1) (amyloid β sheets) and 1639 cm(-1) (β sheets/unordered). We also describe the parallel/antiparallel organization of the β strands. As the inclusions enriched in both β sheets and β sheets/unordered structures are characteristic of severely affected brain regions, we conclude that this kind of amyloid inclusions is likely to be particularly toxic to neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / analysis*
  • Brain / pathology*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / pathology*
  • Nerve Tissue Proteins / analysis*
  • Protein Structure, Secondary
  • Spectrophotometry, Infrared / instrumentation*
  • Synchrotrons / instrumentation*


  • Amyloid
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins