Huntington's Disease is a Disorder of the Corpus Striatum: Focus on Rhes (Ras Homologue Enriched in the Striatum)

Despite identification of the gene for huntingtin (Htt) as causal in Huntington's Disease (HD), explication of HD symptoms and selective damage to the corpus striatum has been elusive. The small G protein Rhes Ras homolog enriched in striatum, highly localized to the striatum, binds selectively to mutant Htt (mHtt) and enhances sumoylation of mHtt. Sumoylation disaggregates mHtt and augments its cytotoxicity. Thus, it appears likely that Rhes-mHtt interaction accounts in substantial part for the selective striatal neurotoxicity of HD with associated extrapyramidal symptomatology. Rhes also binds and activates mTOR, enhancing its influence on protein synthesis, and may be the principal determinant of striatal mTOR activation. In HD, sequestration of Rhes by mHtt may decrease its access to mTOR. The attendant loss of protein translational stimulation may explain the pronounced striatal atrophy of HD. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.