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SUMO modification of Huntingtin and Huntington's disease pathology.

Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.

Pubmed ID: 15064418


  • Steffan JS
  • Agrawal N
  • Pallos J
  • Rockabrand E
  • Trotman LC
  • Slepko N
  • Illes K
  • Lukacsovich T
  • Zhu YZ
  • Cattaneo E
  • Pandolfi PP
  • Thompson LM
  • Marsh JL


Science (New York, N.Y.)

Publication Data

April 2, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA-62203
  • Agency: NICHD NIH HHS, Id: HD36049
  • Agency: NICHD NIH HHS, Id: HD36081

Mesh Terms

  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Cell Nucleus
  • Corpus Striatum
  • Cytoplasm
  • Drosophila
  • Genes, MDR
  • HeLa Cells
  • Humans
  • Huntington Disease
  • Lysine
  • Mutation
  • Nerve Degeneration
  • Nerve Tissue Proteins
  • Neurons
  • Nuclear Proteins
  • Proline
  • Promoter Regions, Genetic
  • Rats
  • Recombinant Fusion Proteins
  • SUMO-1 Protein
  • Transcription, Genetic
  • Transfection
  • Ubiquitin