Mouse models of Huntington disease: variations on a theme

Abstract

An accepted prerequisite for clinical trials of a compound in humans is the successful alleviation of the disease in animal models. For some diseases, however, successful translation of drug effects from mouse models to the bedside has been limited. One question is whether the current models accurately reproduce the human disease. Here, we examine the mouse models that are available for therapeutic testing in Huntington disease (HD), a late-onset neurodegenerative disorder for which there is no effective treatment. The current mouse models show different degrees of similarity to the human condition. Significant phenotypic differences are seen in mouse models that express either truncated or full-length human, or full-length mouse, mutant huntingtin (mHTT). These differences in phenotypic expression may be attributable to the influences of protein context, mouse strain and a difference in regulatory sequences between the mouse Htt and human HTT genes.

Fig. 1.

Comparison of phenotypes between transgenic and knock-in mouse models of HD and human patients. Transgenic YAC mice express human mHTT with its regulatory sequences and exhibit an earlier and more severe phenotype than knock-in mice, which express the CAG expansion in the context of the mouse Htt gene. References: *Graham et al., 2006; ^†Slow et al., 2003; ^#Van Raamsdonk et al., 2005b; ^§Lerch et al., 2008; **Heng et al., 2007; ^††Pouladi et al., 2009; ^##Tang et al., 2007.