Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease?
Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease?
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DOI：
10.1093/hmg/9.17.2539
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发表时间：
2000-10-12
影响因子：
3.5
通讯作者：
Shelbourne, PF
中科院分区：
文献类型：
--
作者：
Kennedy, L;Shelbourne, PF
编码广泛表达的蛋白亨廷顿蛋白内的多聚谷氨酰胺延伸的不稳定CAG三联体重复扩增是引起亨廷顿病（HD）的原因。通过定量的重复大小的个体突变等位基因的组织来源于一个准确的遗传小鼠模型的HD，我们表明，突变变得非常不稳定的纹状体组织。扩增偏向的变化随着年龄的增长而增加，例如来自老年HD小鼠的一些纹状体细胞含有大小增加两倍的突变。如果这种重复不稳定的模式在人纹状体组织中重现，则伴随的多聚谷氨酰胺负荷增加可能导致HD中选择性神经元细胞死亡的模式。我们的研究结果还表明，三核苷酸重复不稳定性可能发生的机制是不复制为基础的。
An unstable CAG triplet repeat expansion encoding a polyglutamine stretch within the ubiquitously expressed protein huntingtin is responsible for causing Huntington's disease (HD). By quantifying the repeat sizes of individual mutant alleles in tissues derived from an accurate genetic mouse model of HD we show that the mutation becomes very unstable in striatal tissue. The expansion-biased changes increase with age, such that some striatal cells from old HD mice contain mutations that have tripled in size. If this pattern of repeat instability is recapitulated in human striatal tissue, the concomitant increased polyglutamine load may contribute to the patterns of selective neuronal cell death in HD. Our findings also suggest that trinucleotide repeat instability can occur by mechanisms that are not replication-based.