Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases

Nat Cell Biol. 2007 Apr;9(4):402-14. doi: 10.1038/ncb1553. Epub 2007 Mar 25.


Nuclear dysfunction is a key feature of the pathology of polyglutamine (polyQ) diseases. It has been suggested that mutant polyQ proteins impair functions of nuclear factors by interacting with them directly in the nucleus. However, a systematic analysis of quantitative changes in soluble nuclear proteins in neurons expressing mutant polyQ proteins has not been performed. Here, we perform a proteome analysis of soluble nuclear proteins prepared from neurons expressing huntingtin (Htt) or ataxin-1 (AT1) protein, and show that mutant AT1 and Htt similarly reduce the concentration of soluble high mobility group B1/2 (HMGB1/2) proteins. Immunoprecipitation and pulldown assays indicate that HMGBs interact with mutant AT1 and Htt. Immunohistochemistry showed that these proteins were reduced in the nuclear region outside of inclusion bodies in affected neurons. Compensatory expression of HMGBs ameliorated polyQ-induced pathology in primary neurons and in Drosophila polyQ models. Furthermore, HMGBs repressed genotoxic stress signals induced by mutant Htt or transcriptional repression. Thus, HMGBs may be critical regulators of polyQ disease pathology and could be targets for therapy development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Death
  • Cells, Cultured
  • Drosophila
  • Electrophoresis, Gel, Two-Dimensional
  • HMGB1 Protein / analysis
  • HMGB1 Protein / metabolism
  • HMGB1 Protein / physiology*
  • HMGB2 Protein / analysis
  • HMGB2 Protein / metabolism
  • HMGB2 Protein / physiology*
  • Immunohistochemistry
  • Immunoprecipitation
  • Models, Biological
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Proteins / analysis
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Binding
  • Proteomics / methods*
  • Purkinje Cells / cytology
  • Purkinje Cells / metabolism
  • RNA, Small Interfering
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • HMGB1 Protein
  • HMGB2 Protein
  • Nuclear Proteins
  • Peptides
  • RNA, Small Interfering
  • polyglutamine