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Science 5 June 2009:
Vol. 324. no. 5932, pp. 1327 - 1330
DOI: 10.1126/science.1172871
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Reports

Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity

Srinivasa Subramaniam, Katherine M. Sixt, Roxanne Barrow, Solomon H. Snyder*

Huntington’s disease (HD) is caused by a polyglutamine repeat in the protein huntingtin (Htt) with mutant Htt (mHtt) expressed throughout the body and similarly in all brain regions. Yet, HD neuropathology is largely restricted to the corpus striatum. We report that the small guanine nucleotide–binding protein Rhes, which is localized very selectively to the striatum, binds physiologically to mHtt. Using cultured cells, we found Rhes induces sumoylation of mHtt, which leads to cytotoxicity. Thus, Rhes-mHtt interactions can account for the localized neuropathology of HD.

The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

* To whom correspondence should be addressed. E-mail: ssnyder{at}jhmi.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)