Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum.
Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum.
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DOI：
10.1093/hmg/ddg056
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发表时间：
2003-02
影响因子：
3.5
通讯作者：
V. Wheeler;Lori-Anne Lebel;V. Vrbanac;Allison M Teed;H. te Riele;M. MacDonald
中科院分区：
文献类型：
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作者：
V. Wheeler;Lori-Anne Lebel;V. Vrbanac;Allison M Teed;H. te Riele;M. MacDonald
编码突变亨廷顿蛋白中多聚谷氨酰胺束的扩展HD CAG重复的体细胞不稳定性与亨廷顿病（HD）病理学的纹状体选择性有关。在Hdh（Q111）小鼠中，我们测试了Msh 2基因缺陷的遗传背景是否会改变预测迟发性神经变性的显性疾病表型的时间或纹状体特异性，Msh 2基因缺陷有望消除插入小鼠HD基因的109 CAG阵列的不稳定行为。我们对Hdh（Q111/+）：Msh 2（+/+）和Hdh（Q111/+）：Msh 2（-/-）后代的分析表明，虽然遗传不稳定性涉及Msh 2依赖性和非依赖性机制，但Msh 2的缺乏足以消除纹状体中进行性HD CAG重复扩增。Msh 2的缺乏也消除了纹状体突变亨廷顿蛋白与体细胞扩大谷氨酰胺束，并导致约5个月的延迟核突变蛋白的积累，但没有改变这种早期表型的纹状体特异性。因此，体细胞HD CAG不稳定性似乎是纹状体选择性疾病过程的结果，该疾病过程通过突变亨廷顿蛋白中谷氨酰胺束的扩展加速早期疾病表型的时间。因此，Msh 2作为精确遗传HD小鼠模型中早期疾病发作的显著修饰剂，为旨在减缓人类发病机制的药理学药物的开发提供了新的靶标。
Somatic instability of expanded HD CAG repeats that encode the polyglutamine tract in mutant huntingtin has been implicated in the striatal selectivity of Huntington's disease (HD) pathology. Here in Hdh(Q111) mice, we have tested whether a genetic background deficient in Msh2, expected to eliminate the unstable behavior of the 109 CAG array inserted into the murine HD gene, would alter the timing or striatal specificity of a dominant disease phenotype that predicts late-onset neurodegeneration. Our analyses of Hdh(Q111/+):Msh2(+/+) and Hdh(Q111/+): Msh2(-/-) progeny revealed that, while inherited instability involved Msh2-dependent and -independent mechanisms, lack of Msh2 was sufficient to abrogate progressive HD CAG repeat expansion in striatum. The absence of Msh2 also eliminated striatal mutant huntingtin with somatically expanded glutamine tracts and caused an approximately 5 month delay in nuclear mutant protein accumulation, but did not alter the striatal specificity of this early phenotype. Thus, somatic HD CAG instability appears to be a consequence of a striatal-selective disease process that accelerates the timing of an early disease phenotype, via expansion of the glutamine tract in mutant huntingtin. Therefore Msh2, as a striking modifier of early disease onset in a precise genetic HD mouse model, provides a novel target for the development of pharmacological agents that aim to slow pathogenesis in man.