Rhes, a protein with selective expression in the striatum, plays a major role in Huntington's disease pathogenesis

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreiform movements, cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt). The genetic defect encodes a polyglutamine tract in the N-terminal part of Ht t that confers a toxic function to the protein. The most striking neuropathological hallmark in HD patients is the selective atrophy of the striatum. The mechanisms underlying the particular vulnerability of the striatum are unknown. Subramaniam and collaborators demonstrate that the cytotoxicity of mutant Htt is greatly enhanced in the presence of the small GTPase, Rhes, a protein of unclear function that has a preferential expression in the striatum. The study demonstrates that Rhes is an E3 ligase, interacts with mutant Htt and modifies it through SUMOylation, a post-transcriptional process that consists of the addition of the protein SUMO1 to mutant Htt. By contrast, the GTPase activity of Rhes does not seem to be involved in the toxicity of mutant Htt. The Rhesmediated sumoylation of mutant Htt eventually leads to reduced levels of neuroprotective insoluble aggregates, and increased levels of the toxic soluble form of mutant Htt. These completely novel results shed new light on HD pathogenesis. The selective expression of Rhes in the striatum and its role in mutant Htt toxicity could explain why the striatum is so vulnerable in HD. This work may lead to new therapeutic strategies targeting Rhes.