Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases

Mol Cell Neurosci. 2007 Jan;34(1):10-9. doi: 10.1016/j.mcn.2006.09.006. Epub 2006 Nov 7.

Abstract

Polyglutamine diseases are characterized by neuronal intranuclear inclusions of expanded polyglutamine proteins, which are also ubiquitinated, indicating impairment of the ubiquitin-proteasome system. E2-25K (Hip2), an ubiquitin-conjugating enzyme, interacts directly with huntingtin and may mediate ubiquitination of the neuronal intranuclear inclusions in Huntington disease. E2-25K could thus modulate aggregation and toxicity of expanded huntingtin. Here we show that E2-25K is involved in aggregate formation of expanded polyglutamine proteins and polyglutamine-induced cell death. Both a truncated mutant, lacking the catalytic tail domain, as well as a full antisense sequence, reduce aggregate formation. Strikingly, both E2-25K mutants also reduced polyglutamine-induced cell death. In postmortem brain material of both Huntington disease and SCA3, E2-25K staining of polyglutamine aggregates was observed in a subset of neurons bearing intranuclear neuronal inclusions. These results demonstrate that targeting by ubiquitination plays an important role in the pathology of polyglutamine diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / enzymology*
  • Brain / pathology
  • Brain / physiopathology
  • Catalytic Domain / genetics
  • Cell Death / genetics
  • Cell Line, Tumor
  • Humans
  • Huntingtin Protein
  • Huntington Disease / enzymology
  • Huntington Disease / genetics
  • Huntington Disease / physiopathology
  • Intranuclear Inclusion Bodies / enzymology*
  • Intranuclear Inclusion Bodies / genetics
  • Intranuclear Inclusion Bodies / pathology
  • Machado-Joseph Disease / enzymology
  • Machado-Joseph Disease / genetics
  • Machado-Joseph Disease / physiopathology
  • Mutation / genetics
  • Nerve Degeneration / enzymology*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / physiopathology
  • Nerve Tissue Proteins / metabolism
  • Neurons / enzymology*
  • Neurons / pathology
  • Nuclear Proteins / metabolism
  • Peptides / genetics
  • Peptides / metabolism*
  • Ubiquitin-Conjugating Enzymes / chemistry
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism*

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • polyglutamine
  • UBE2K protein, human
  • Ubiquitin-Conjugating Enzymes