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Science 2 April 2004:
Vol. 304. no. 5667, pp. 100 - 104
DOI: 10.1126/science.1092194
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Reports

SUMO Modification of Huntingtin and Huntington's Disease Pathology

Joan S. Steffan,1 Namita Agrawal,2 Judit Pallos,2 Erica Rockabrand,1 Lloyd C. Trotman,3 Natalia Slepko,2 Katalin Illes,1 Tamas Lukacsovich,2 Ya-Zhen Zhu,1 Elena Cattaneo,4 Pier Paolo Pandolfi,3 Leslie Michels Thompson,1,5* J. Lawrence Marsh2*{dagger}

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.

1 Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA 92697, USA.
2 Department of Developmental and Cell Biology, 4444 McGaugh Hall, University of California, Irvine, CA 92697, USA.
3 Molecular Biology Program and Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
4 Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.
5 Department of Biological Chemistry, D240 Medical Sciences I, University of California, Irvine, CA 92697, USA.



* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jlmarsh{at}uci.edu

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