title: SUMO modification of Huntingtin and Huntington's disease pathology.
abstract: 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.
authors.affiliation: Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA 92697, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
authors.forename: Namita
authors.initials: N
authors.lastname: Agrawal
authors.forename: Judit
authors.initials: J
authors.lastname: Pallos
authors.forename: Erica
authors.initials: E
authors.lastname: Rockabrand
authors.forename: Lloyd C
authors.initials: LC
authors.lastname: Trotman
authors.forename: Natalia
authors.initials: N
authors.lastname: Slepko
authors.forename: Katalin
authors.initials: K
authors.lastname: Illes
authors.forename: Tamas
authors.initials: T
authors.lastname: Lukacsovich
authors.forename: Ya-Zhen
authors.initials: YZ
authors.lastname: Zhu
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology; D003593:Cytoplasm / Q000378:metabolism; D004330:Drosophila; D019450:Genes, MDR; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D025801:Ubiquitin; D011392:Proline; D008239:Lysine