NEW YORK (Reuters Health) - Attaching small ubiquitin-like modifier (SUMO)-1 to Huntingtin (Htt), the pathogenic protein of Huntington’s disease, appears to increase the protein’s ability to cause neurodegeneration, new research suggests.
“SUMO-1 seems to play an important role in disease progression, and this study points to new avenues of therapy that bring us closer to being able to target the cause rather than the symptoms of this devastating disease,” senior author Dr. J. Lawrence Marsh, from the University of California at Irvine, said in a statement.
The findings, which appear in the April 2nd issue of Science, are based on a study of SUMO-1’s effects in cultured cells and in a Drosophila model of Huntington’s disease.
Attaching SUMO-1 to the pathogenic fragment of Htt stabilized the protein, making it less likely to form aggregates and enhancing its ability to repress transcription, the researchers report.
In the Drosophila model, the SUMO-1 modification increased the nerve destruction seen. In contrast, attaching ubiquitin to Htt abrogated the neurodegeneration, the investigator point out.
Lastly, the authors found that introducing lysine mutations on Htt, which prevents the binding of both SUMO-1 and ubiquitin, reduced Huntington’s disease pathology. This indicates that “the contribution of SUMOylation to Huntington’s disease pathology extends beyond preventing Htt ubiquitination and degradation,” the researchers note.
“From a therapeutic standpoint, it is possible that decreasing expression of the SUMO-1 precursor, inhibiting SUMO-1 ligases, or increasing isopeptidase activity to remove SUMO-1 could reduce the level of SUMOylated Htt in neurons and suppress Huntington’s disease pathogenesis,” they add.
Source: Science 2004;304:100-104. [ Google search on this article ]
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