Transgenic Rodent Models of Huntington Disease

A number of neurodegenerative disorders, including Huntington's disease (HD), are caused by the expansion of polymorphic tracts of CAG repeats (coding for consecutive glutamine residues) within a diverse set of genes. Although the type of genetic mutation is similar among these disorders, the populations of affected neurons, the clinical syndromes, and the neuropathological lesions are quite distinct for each disorder. Each of the CAG repeat disorders is associated with a distinct gene product. Like the other CAG repeat disorders, HD is progressively debilitating, ultimately leading to death over a protracted (15 to 25 years) period. The symptoms of HD include motor dysfunction, cognitive changes that progress to dementia, and psychiatric disturbances. The HD gene is initially localized to the short arm of chromosome 4 by standard linkage analyses and subsequently identified by the presence of the CAG repeat expansion in exon 1 of the Huntingtin (htt) gene. Studies of transgenic animals that express variants of mutant htt provide insight into the pathogenesis of HD. Indeed, single cell PCR studies suggest that htt is more highly expressed in interneurons of the striatum than in the medium spiny neurons, which are more vulnerable population. Subcellularly, htt can be found throughout neuronal cell bodies but may be more enriched in nerve terminals and vesicles.