Shelbourne Peggy F, Keller-McGandy Christine, Bi Wenya Linda, Yoon Song-Ro, Dubeau Louis, Veitch Nicola J, Vonsattel Jean Paul, Wexler Nancy S, Arnheim Norman, Augood Sarah J
Hum Mol Genet. 2007 May 15;16(10):1133-42. doi: 10.1093/hmg/ddm054. Epub 2007 Apr 4.
Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.
亨廷顿舞蹈症是由一个CAG重复序列的扩增引起的，该重复序列编码一种名为亨廷顿蛋白的蛋白质中一段延长的谷氨酰胺序列。在此，我们提供证据支持以下假说：体细胞中突变长度的增加在亨廷顿舞蹈症发病机制的进行性本质和细胞选择性方面发挥作用。从人类亨廷顿舞蹈症病例和基因敲入型亨廷顿舞蹈症小鼠获取的显微切割组织和单个激光切割细胞的结果表明，尽管神经元的突变长度增加往往比神经胶质细胞更长，但在所有测试的细胞类型中CAG重复序列都是不稳定的。突变长度增加在疾病过程早期就会出现，并随着疾病进展持续积累。与观察到的细胞丢失模式一致，在低级别人类亨廷顿舞蹈症病例中，纹状体神经元的突变长度增加往往比皮质更明显，在更晚期病例中则不太明显。有趣的是，亨廷顿舞蹈症小鼠的神经元亚群似乎对突变长度增加有不同的倾向；特别是，与全纹状体神经元群体相比，一氧化氮合酶阳性的纹状体中间神经元（亨廷顿舞蹈症中相对未受影响的细胞类型）的突变长度增加较小。更普遍地说，数据表明亨廷顿舞蹈症中重复长度的神经元变化至少与种系中观察到的变化一样大，甚至可能更大。在非复制细胞中发生显著的CAG重复长度增加这一事实也表明，诸如不适当的错配修复而非DNA复制等过程参与了亨廷顿舞蹈症脑组织中突变不稳定性的产生。
