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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.

Huntington’s disease (HD) is caused by a genetic mutation of the IT-15 gene resulting in the expansion of the trinucleotide CAG in the huntingtin protein (MacDonald et al., 2003). The mechanism(s) by which this expanded protein causes the disease remains unknown, and there is currently no treatment to halt or prevent development of the disease. An assay was designed to measure the ability of three neurotrophic peptides (Colivelin, D-SAL, D-NAP) to protect cultured PC12 cells from death caused by an expanded form of human huntingtin exon 1. Each neurotrophic peptide was tested at six concentrations for its ability to protect cells against huntingtin-induced cell death. Cell viability was determined by an LDH activity assay that measured the change in absorbance over time. Neurotrophic peptides Colivelin and D-SAL promoted cell viability in both treatment types tested whereas D-NAP only promoted cell viability in the twenty-four hour pre-incubation treatment type.