Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a 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 significantly 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.

Figure 1. Rhes gene deletion significantly delays the onset of HD-induced motor dysfunction.

NC: solid lines; HD: dashed lines; Diamonds: Rhes WT; Squares: Rhes Het; Circles: Rhes KO.

Figure 2. Dystonia as indicated by Limb Adduction.

Legend is the same as for Fig. 1. Ordinate gives the average number of limbs drawn inward toward the body (labeled “Limb Adduction”) during three trials repeated monthly for the 6 months of observation.

Figure 3. Post-mortem Brain Weight in mg.

Black bars = NC; white bars = HD. Both Rhes and HD were significant factors in diminishing brain weight. However, a combined effect of HD and Rhes KO was not seen in HD/KO mice, indicating a protective effect of Rhes deletion on brain weight in these mice.

Figure 4. Brain Area (mm²) as a function of genotype.

Legend is the same as in Fig. 3, and the conclusions are the same. Both Rhes and HD were significant factors in diminishing brain weight. However, a combined effect of HD and Rhes KO was not seen in HD/KO mice, indicating a protective effect of Rhes deletion on brain area loss in these mice.