| 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. |
| Keywords: |
controlled study; protein expression; unclassified drug; human cell; promoter region; genetics; mutation; pathogenesis; nonhuman; ubiquitin; protein function; protein localization; proteins; protein analysis; animal; cytology; metabolism; animals; gene; nuclear protein; protein degradation; cell line; nerve tissue proteins; protein; drosophila; genetic transcription; neurons; transcription, genetic; pathology; hela cell; hela cells; transfection; transgenic animal; nuclear proteins; chemistry; hybrid protein; genetic transfection; recombinant fusion proteins; rat; cytoplasm; rats; cell nucleus; sumo protein; sumo-1 protein; nerve protein; nerve cell; medicine; diseases; lysine; corpus striatum; protein modification; proline; nerve degeneration; cells; degradation; sumo 1 protein; animals, genetically modified; huntington chorea; huntington disease; promoter regions (genetics); genes, mdr; polyglutamine; humans; human; priority journal; article; pathogenic fragment; pathogenic protein; huntingtin; protein httex1p; hd protein, human; hdh protein, rat
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