Dragileva Ella, Hendricks Audrey, Teed Allison, Gillis Tammy, Lopez Edith T, Friedberg Errol C, Kucherlapati Raju, Edelmann Winfried, Lunetta Kathryn L, MacDonald Marcy E, Wheeler Vanessa C
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston MA 02114, USA.
Neurobiol Dis. 2009 Jan;33(1):37-47. doi: 10.1016/j.nbd.2008.09.014. Epub 2008 Sep 30.
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.
改变亨廷顿舞蹈症（HD）的CAG重复序列长度是一种颇具吸引力的治疗方法，该重复序列长度是疾病发病年龄的主要决定因素。为了探索这一点，我们正在研究代际间和体细胞HD CAG重复序列不稳定性的机制。在此，我们已将HD CAG基因敲入小鼠与错配修复基因Msh3和Msh6缺陷的背景小鼠杂交，以识别对CAG重复序列大小和疾病发病机制的影响。我们发现，不同机制在遗传和体细胞不稳定性中占主导地位，Msh6可防止代际间收缩，而Msh3对于增加CAG长度以及增强纹状体中的早期疾病表型均是必需的。因此，试图减小遗传重复序列大小可能需要全面了解Msh6复合物，而试图阻止纹状体神经元中CAG大小随年龄增长的增加以及减缓疾病进程将需要全面阐明Msh3复合物及其在CAG重复序列不稳定性中的功能。
