SUMO Modification of Huntingtin and Huntington's Disease Pathology

By J. Steffan, N. Agrawal, J. Pallos, E. Rockabrand, L. Trotman, N. Slepko, K. Illes, T. Lukácsovich, Ya-zhen Zhu, E. Cattaneo and 3 more. Science, 2004

757 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6c17bac61955a6e90a36c51fa04d07c2e7779b6c

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Citations in the corpus

The Fly as a Model for Neurodegenerative Diseases: Is It Worth the Jump? (2007, positive): “Furthermore, acting on in vitro evidence showing that Httex1p can be modified either by small ubiquitin-like modifier (SUMO) 1 or by ubiquitin on identical lysine residues, the same group found that abolishing Httex1p lysine residues or lowering SUMOylation activity suppressed neurodegeneration wher”
SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? (2004, background): “…and genetic manipulation of the SUMO conjugation pathway in Drosophila indicates that SUMOylation contributes to neurodegeneration in at least two polyglutamine repeat diseases, spinal and bulbar muscular atrophy (SBMA) and Huntington’s (Chan et al. 2002; Li et al. 2003; Steffan et al. 2004).”
Molecular mechanisms and potential therapeutical targets in Huntington's disease. (2010, background): “Sumoylation modulates its subcellular localization, activity, and stability (204, 549) (see Fig.”
Modification of proteins by ubiquitin and ubiquitin-like proteins. (2006, background): “For example, ubiquitin modification of the Huntingtin (Htt) protein correlates with reduced neurodegeneration, whereas SUMO modification of the same Htt lysines inhibits aggregate formation in cultured cells and exacerbates symptoms in a Drosophila model (Steffan et al. 2004).”
Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, background): “…of mHtt-induced oxidative stress (Wyttenbach et al., 2002; Giuliano et al., 2003; Lu et al., 2014), huntingtin posttranscriptional modifications (Steffan et al., 2004; Greiner and Yang, 2011; Bhat et al., 2014; Pavese et al., 2006), microglia activation (Gusella and MacDonald, 2009), a…”