Molecular neurobiological analyses of Huntington's disease model mouse

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movement, personality change, and dementia. We have generated HD gene knock-in mice in which the exon 1 of the mouse HD gene was replaced by the human exon 1 containing 77CAG repeats. Wild and mutated huntingtin proteins were expressed ubiquitously in brain and peripheral tissues. To determine the number of CAG repeats, genescan-analysis was performed using genomic DNA prepared from various tissues. Instability of CAG repeats through meiotic transmission is considered to be implicated in their expansion and a mouse identified with 97 CAG repeats in exon 1 of mouse HD gene was mated with homozygous (77 CAG repeat, male) and normal mice (female). In addition, a one or two CAG repeat expansion was found in 25% of the litters from paternal transmission. The CAG repeat in 20% litters, by contrast, was contracted by maternal transmission. Expanded CAG repeat instability (somatic CAG mosaicism) in 30 week-old mice was found in brain except for the cerebellum, and in peripheral organs such as the liver, kidney and stomach. We confirmed the same results of expanded CAG repeat instability in human brain of HD patients. The CAG repeat instability of this mouse model may mirror the abnormalities in HD patients.