The Rhes is Htt-ory
Expansion of a polyglutamine repeat in the huntingtin (Htt) protein generates a mutant form (mHtt) that causes Huntington's disease (HD), a neurodegenerative disease that mainly affects the corpus striatum. mHtt can be modified by sumoylation, which increases the soluble, more toxic form of mHtt at the expense of the aggregated, cyto-protective form. Rhes is small G protein, homologous to Ras, that binds both Htt and mHtt and is named based on its selective localization to the striatum (Ras homolog enriched in striatum). To define how Rhes may affect mHtt and HD, Subramaniam et al. tested its role in mHtt-mediated cytotoxicity and mHtt modification. They found that overexpressing Rhes augmented mHtt sumoylation, providing an explanation for their earlier observations that overexpression of Rhes increased the levels of soluble mHtt and apoptosis. In vitro experiments further implicated Rhes directly as a potential E3 ligase in the sumoylation of mHtt, the first G protein to be implicated as such. Farnesylation of Rhes was required for sumoylation and disaggregation of mHtt, its cytotoxicity upon overexpression, and its attachment to the plasma membrane. These results help explain why HD mainly affects the striatum even though mHtt has broad tissue distribution. (Science 324, 1327–1330, 2009) MB
This is a preview of subscription content, access via your institution