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Rhes (Ras homolog enriched in striatum) has been identified as a novel monomeric G-protein involved in dopaminergic and other signaling in the striatum. Given the many effects of opioids that involve striatal circuitry, genetically engineered mice that are incapable of making Rhes (rhes-/-) and their control littermates (rhes+/+) were subjected to behavioral tests to determine if any differences existed in opioid analgesia, tolerance, withdrawal, reward, and locomotion. Rhes-/- mice showed an increased opioid mediated analgesia, along with an absence of tolerance and decrease in withdrawal when compared with rhes+/+ littermates. However, no significant changes were seen in opioid induced locomotor activation or conditioned place preference. These results provide strong evidence for the implication of Rhes in opioid signaling.

Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is untreatable, incurable, and ultimately fatal. HD is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein (mHtt) is ubiquitously expressed in HD patients, cellular degeneration occurs only in neurons within the striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent work using cultured cells suggests that Rhes may be a co-factor with mHtt in cell death. However, there is controversy as to whether cell death underlies the symptoms of HD. We used a validated transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD/Rhes-/- mice showed greatly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.

Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. The progressive disease is caused by an unstable CAG expansion within the gene that normally encodes for the huntingtin protein (Htt). The expanded mutant form of Htt (mHtt) is expressed ubiquitously throughout patients’ bodies; however, neuronal degeneration is prominent only in the corpus striatum and, to a lesser extent, the cortex. The Ras homolog Rhes is also preferentially localized to the striatum. The putative co-factor Rhes has been shown to act with mHtt to cause neuronal death. Simvastatin, a lipid lowering drug, and zoledronate, a nitrogen bisphosphonate, act on the mevalonate pathway, which gives both Rhes and its target cells, binding sites. The current study aimed to interrupt the mevalonate pathway and inactivate, via de-prenylation, Rhes in CD-1 mice exposed to 3-nitroproprionic acid, a neurotoxin that mimics HD mitochondrial dysfunction and striatal degeneration. Results suggest that drug treatment does not rescue motor impairments and may potentiate 3-NP damage. The persistent motor deficits are discussed in relation to possible Rhes de-prenylation.

Located on the short arm of chromosome 4, there exists a gene, IT15, responsible for the trinucleotide CAG expansion involved in the autosomal dominant neurodegenerative disorder known as Huntington’s disease (HD). The brain region associated with the most atrophy, the striatum, leads to expression of severe motor dysfunction, the hallmark feature of HD. To a lesser degree, the cortex and hippocampus show earlier deterioration indicative of the cognitive deficits that occur prior to motor symptom onset. The brain regions associated with HD-induced neuronal death additionally selectively express the protein Rhes - the combination of Rhes and mutant huntingtin being cytotoxic. Using a 3-nitropropionic acid animal model of HD, we hypothesized that animals with preserved prenylation of Rhes would display cognitive and motor symptomology similar to genetic models of HD while animals administered statins or bisphosphonates would show inhibited Rhes prenylation and delayed cognitive symptoms. Experimental animals, however, did not perform differently than control animals on shallow water variants of the t-maze and MWM.

Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. An unstable CAG expansion within the gene normally encoding for the Huntingtin protein is responsible. The expanded mutant form of Huntingtin and the putative protein co-factor Rhes interact and cause cell death within the striatum. We hypothesized chronic treatment with simvastatin, a cholesterol lowering drug, would disrupt the biosynthetical pathway which gives both Rhes and its target cells binding sites and render Rhes inactive. Healthy and HD mice were treated with simvastatin or a vehicle. Animals’ motor behavior was assessed with three separate tests over the first four months of life. No significant differences were found between the HD groups; however, the HD treated animals’ performance on the rotarod test, at month 4, was intermediate between healthy mice and HD vehicle treated mice. The results hint at simvastatin’s therapeutic potential, but are interpreted cautiously.

Huntington’s disease is an incurable, progressive neurological disorder characterized by loss of motor control, psychiatric dysfunction, and eventual dystonia leading to death. Despite the fact that this disorder is caused by a mutation in one single gene, there is no cure. The mutant Huntingtin (mHtt) protein is expressed ubiquitously throughout the brain but frank cell death is limited to the striatum. Recent work has suggested that Rhes, Ras homolog enriched in striatum, which is selectively expressed in the striatum, may play a role in Huntington’s disease neuropathology. In vitro studies have shown Rhes to be an E3 ligase for the post-translational modification protein SUMO. Rhes increases binding of SUMO to mHtt which competes for the same binding site as Ubiquitin. SUMOylation of mHtt leads to disaggregation and cellular death, whereas ubiquitination leads to aggregation and cellular protection. In a previous study we showed that deletion of Rhes caused a decrease in the Huntington’s disease phenotype in mice. We hypothesized that mice lacking Rhes would also show increased aggregation in the striatum and this increased aggregation would correlate in a rescue of behavioral symptoms. Despite the prior in vitro and in vivo evidence, deletion of Rhes in vivo did not alter the aggregation of mHtt in the striatum of mice however deletion of Rhes still showed a rescue from the diseased phenotype. This result would indicate that deletion of Rhes alters the neurobehavioral phenotype of Huntington’s disease through a different pathway than promoting aggregation in striatal cells.