The role of Rhes, Ras homolog enriched in striatum, in neurodegenerative processes.

Rhes is a small GTPase whose expression is highly enriched in striatum. It shares homology with Ras proteins, but also contains a C-terminal extension, thus suggesting additional functions. Signaling by 7 transmembrane receptors through heterotrimeric G proteins is inhibited by Rhes. However, perhaps the most remarkable feature of this small GTPase described thus far is that it can account for the selective vulnerability of the striatum in Huntington's Disease (HD). HD is an autosomal dominant neurodegenerative disease caused by a poly-glutamine expansion in the protein huntingtin. Despite the presence of huntingtin throughout the brain and the rest of the body, the striatum is selectively degenerated. Recent work shows that Rhes acts as an E3 ligase for attachment of SUMO (small ubiquitin-like modifier). As this post-translational modification decreases the formation of huntingtin aggregates and promotes cell death, this property of Rhes offers an explanation for selective striatal vulnerability in HD. In addition, the sequestering of Rhes through its binding to mutant huntingtin may decrease the ability of Rhes to perform vital physiological functions in the neuron. Thus, as Rhes is an attractive candidate for HD therapy, a thorough understanding of its physiological functions will allow for specific targeting of its pathological functions.