Is the ubiquitin-proteasome system impaired in Huntington's disease?

Cell Mol Life Sci. 2007 Sep;64(17):2245-57. doi: 10.1007/s00018-007-7222-8.


Ubiquitylated inclusion bodies (IBs) found in Huntington's disease (HD) postulate an impaired ubiquitin-proteasome system. However, this hypothesis remains controversial. In vitro-generated polyglutamine aggregates failed to inhibit purified proteasomes, while filamentous huntingtin aggregates isolated from mice resulted in inhibition. However, similarly isolated IBs did not, thus suggesting that IB formation is protective by sequestering smaller inhibitory aggregates. Accordingly, proteasome-activity assays in IB-containing mouse brain homogenates did not show decreased activity. On the contrary, some of the endoproteolytic proteasome activities increased, probably due to altered subunit composition. However, activity was found decreased in postmortem human HD tissue. Finally, evidence supporting the hypothesis was found in HD cell models expressing fluorescent ubiquitin-proteasome system reporters but not in retina of SCA-7 mice with similar reporters. In summary, it seems that mutant huntingtin, probably in intermediate aggregate forms, has the potential to inhibit proteasome activity, but the global status of the system in HD brain tissue is not yet fully elucidated.

Publication types

  • Review

MeSH terms

  • Animals
  • Genes, Reporter
  • Humans
  • Huntingtin Protein
  • Huntington Disease / enzymology*
  • Luminescent Proteins / analysis
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Endopeptidase Complex / physiology*
  • Proteasome Inhibitors
  • Ubiquitin / physiology*


  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proteasome Inhibitors
  • Ubiquitin
  • Proteasome Endopeptidase Complex