Molecular neurobiological analyses of Huntington's disease model mouse

亨廷顿病（HD）是一种常染色体显性遗传的神经退行性疾病，其特征在于不自主运动、人格改变和痴呆。我们已经产生了HD基因敲入小鼠，其中小鼠HD基因的外显子1被包含77个CAG重复的人外显子1替换。野生型和突变型亨廷顿蛋白在脑和外周组织中广泛表达。为了确定CAG重复序列的数量，使用从各种组织制备的基因组DNA进行基因扫描分析。通过减数分裂传递的CAG重复序列的不稳定性被认为与其扩增有关，并且将在小鼠HD基因的外显子1中鉴定为具有97个CAG重复序列的小鼠与纯合子（77个CAG重复序列，雄性）和正常小鼠（雌性）交配。此外，一个或两个CAG重复扩增被发现在25%的窝从父亲传播。CAG重复在20%的窝，相比之下，由母体传播收缩。在30周龄的小鼠中，在除小脑之外的脑中以及在外周器官如肝、肾和胃中发现了扩展的CAG重复不稳定性（体细胞CAG嵌合体）。我们证实了同样的结果，扩大CAG重复不稳定性在人类大脑的血液透析患者。该小鼠模型的CAG重复不稳定性可能反映了HD患者的异常。

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.