Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes.
Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes.
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DOI：
10.1016/j.nbd.2008.09.014
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发表时间：
2009-01
影响因子：
6.1
通讯作者：
Wheeler, Vanessa C.
中科院分区：
文献类型：
--
作者：
Dragileva, Ella;Hendricks, Audrey;Teed, Allison;Gillis, Tammy;Lopez, Edith T.;Friedberg, Errol C.;Kucherlapati, Raju;Edelmann, Winfried;Lunetta, Kathryn L.;MacDonald, Marry E.;Wheeler, Vanessa C.
改变亨廷顿病（HD）CAG重复序列的长度是疾病发作年龄的主要决定因素，是一种有吸引力的治疗方法。为了探索这一点，我们正在研究代际和体细胞HD CAG重复不稳定性的机制。在这里，我们将HD CAG敲入小鼠与错配修复基因Msh3和Msh6缺陷的背景杂交，以辨别对CAG重复序列大小和疾病发病机制的影响。我们发现，不同的机制占主导地位的遗传和体细胞的不稳定性，与Msh6防止代际收缩和Msh3需要增加CAG长度和提高纹状体的早期疾病表型。因此，试图减少遗传性重复序列大小可能需要充分了解Msh6复合物，而试图阻止纹状体神经元中CAG大小的年龄依赖性增加并减缓疾病过程将需要充分阐明Msh3复合物及其在CAG重复序列不稳定性中的功能。
Modifying the length of the Huntington's disease (HD) CAG repeat, the major determinant of age of disease onset, is an attractive therapeutic approach. To explore this we are investigating mechanisms of intergenerational and somatic HD CAG repeat instability. Here, we have crossed HD CAG knock-in mice onto backgrounds deficient in mismatch repair genes, Msh3 and Msh6, to discern the effects on CAG repeat size and disease pathogenesis. We find that different mechanisms predominate in inherited and somatic instability, with Msh6 protecting against intergenerational contractions and Msh3 required both for increasing CAG length and for enhancing an early disease phenotype in striatum. Therefore, attempts to decrease inherited repeat size may entail a full understanding of Msh6 complexes, while attempts to block the age-dependent increases in CAG size in striatal neurons and to slow the disease process will require a full elucidation of Msh3 complexes and their function in CAG repeat instability.
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