Huntington's disease (HD) is a devastating neurodegenerative disease that manifests initially as motor and cognitive dysfunction followed by a relentlessly chronic progression of symptoms culminating in death. The cause of HD is a genetic aberration on the short arm of the 4th chromosome identified as an expansion of a CAG trinucleotide repeat. Molecular biologists have very recently begun developing genetically altered mice, designed to mimic the expanded CAG repeat in HD. Technology advances have created a unique situation whereby development of new lines of mice has outpaced careful behavioral analysis of phenotypes. As a result, numerous models have been created without a clear understanding of how genetic differences affect phenotype differences. Perhaps more importantly, there is currently no consensus on what features of these models best mimic features of the disease they represent. Lacking a clear understanding of behavioral deficits vastly reduces the usefulness of any genetic model designed to mimic a disease that manifests with profound behavioral symptoms. The current proposal is a series of experiments designed to undertake detailed assessment of motor abnormalities and some cognitive dysfunction in mouse models of HD. In particular abnormalities in coordinated limb movements will be assessed beginning at a relatively early age.
The first aim i s to conduct experiments in a model currently known to express other gross behavioral abnormalities later in development. Once methods for assessing early subtle motor/cognitive deficits are established, the second aim is to assess genetically more appropriate models that reportedly express few gross behavioral abnormalities. The long-term objective will be initiated in the third aim where potentially therapeutic drugs will be assessed. Drug therapies that attenuate early/subtle deficits in mice may be useful in treating HD. Such therapeutic potential may not be recognized using current methods that assess only major dysfunction expressed late in development.
