Characterization and use of the YAC128 mouse model of H

Huntington disease (HD) is caused by a CAG expansion in the gene encoding the protein huntingtin and manifests clinically with motor and cognitive impairments and psychiatric disturbances. An accurate animal model is crucial for elucidation of the underlying mechanisms which lead to pathogenesis and also for testing experimental therapeutics. The yeast artificial chromosome (YAC) mouse model expresses full-length human huntingtin with 128 CAG repeats (YAC128) from an endogenous promoter. The YAC128 model accurately recapitulates the age-dependent brain atrophy including cortical and striatal atrophy accompanied by striatal neuronal loss characteristic of HD. The onset of impairments in motor co-ordination, pre-pulse inhibition and cognition, along with a biphasic activity profile composed of initial hyperactivity and late hypoactivity in the YAC128 mice recapitulates the clinical manifestation of the human disease. The accurate recapitulation of the human disorder in the YAC128 mouse allows the utilization of this model to identify the primary events which lead to pathogenesis and target those events for therapeutics. The phenotypes in the YAC128 are robust on multiple background strains, reproducible and demonstrate low inter-animal variability, indicating the YAC128 model is highly suited for use in therapeutic trials.;Huntingtin inclusions or aggregates are present late in the natural history of disease in the YAC128 mouse model, after the onset of both neuronal dysfunction indicated by rotarod deficit and neuronal degeneration, indicated by brain and striatal atrophy. The onset of neuronal degeneration in the YAC128 mice on the B6 strain background is delayed, yet the time course and severity of huntingtin inclusion formation is unaltered. The shortstop mouse expresses a short fragment of huntingtin with the identical CAG size, tissue distribution and level of transgenic protein expression as the full-length YAC128 model. Huntingtin inclusions form earlier and are more prevalent both in number and tissue distribution in the shortstop compared to the full-length YAC128 model. Despite widespread inclusion formation, the shortstop mouse does not manifest the neuronal dysfunction or degeneration present in the full-length YAC128 model. Together, these results demonstrate that huntingtin aggregates are not the direct cause of toxicity in HD and are likely a benign by-product of polyglutamine expansion.