A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice

Huntington's disease (HD) is a dominant disorder characterized by premature and progressive neurodegeneration, In order to generate an accurate model of the disease, we introduced an HD-like mutation (an extended stretch of 7 2-80 CAG repeats) into the endogenous mouse Hdh gene. Analysis of the mutat ion in vivo reveals significant levels of germline instability, with expans ions, contractions and sex-of-origin effects in evidence, Mice expressing f ull-length mutant protein display abnormal social behaviour in the absence of acute neurodegeneration, Given that psychiatric changes, including irrit ability and aggression, are common findings in HD patients, our data are co nsistent with the hypothesis that some clinical features of HD may be cause d by pathological processes that precede gross neuronal cell death, This im plies that effective treatment of HD may require an understanding and ameli oration of these dysfunctional processes, rather than simply preventing the premature death of neurons in the brain. These mice should facilitate the investigation of the molecular mechanisms that underpin the pathway from ge notype to phenotype in HD.