SUMO Modification of Huntingtin and Huntington's Disease Pathology

Steffan, J. S., Agrawal, N., Pallos, J., Rockabrand, E., Trotman, L. C., Slepko, N., Illes, K., Lukacsovich, T., Zhu, Y. Z., Cattaneo, E., Pandolfi, P. P., Thompson, L. M., Marsh, J. L. (April 2004) SUMO Modification of Huntingtin and Huntington's Disease Pathology. Science, 304 (5667). pp. 100-104. ISSN 00368075 (ISSN)

DOI: 10.1126/science.1092194


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.

Item Type: Paper
Uncontrolled Keywords: Cells Degradation Diseases Proteins Pathogenic fragment Pathogenic protein Pathology huntingtin lysine polyglutamine protein protein httex1p SUMO 1 protein SUMO protein unclassified drug HD protein human Hdh protein rat hybrid protein nerve protein nuclear protein proline ubiquitin medicine article controlled study Drosophila human human cell Huntington chorea nerve degeneration nonhuman pathogenesis priority journal protein analysis protein degradation protein expression protein function protein localization protein modification animal cell line cell nucleus chemistry corpus striatum cytology cytoplasm gene genetic transcription genetic transfection genetics HeLa cell metabolism mutation nerve cell promoter region rat transgenic animal Animals Animals, Genetically Modified Genes MDR Hela Cells Humans Huntington Disease Nerve Tissue Proteins Neurons Nuclear Proteins Promoter Regions (Genetics) Rats Recombinant Fusion Proteins SUMO-1 Protein Transcription Genetic Transfection
Subjects: organism description > animal > insect > Drosophila
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
diseases & disorders > cancer > cancer types > huntington's disease
CSHL Authors:
Communities: CSHL labs > Trotman lab
Depositing User: Brian Soldo
Date: 2 April 2004
Date Deposited: 23 Mar 2012 16:08
Last Modified: 08 May 2013 16:44
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