Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease.
Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease.
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DOI：
10.1371/journal.pgen.1005267
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发表时间：
2015-08
期刊：
影响因子：
4.5
通讯作者：
McMurray CT
中科院分区：
文献类型：
--
作者：
Budworth H;Harris FR;Williams P;Lee DY;Holt A;Pahnke J;Szczesny B;Acevedo-Torres K;Ayala-Peña S;McMurray CT
亨廷顿病 (HD) 是由单个疾病长度等位基因的遗传引起的，该等位基因含有扩展的 CAG 重复序列，随着年龄的增长，该重复序列在体组织中继续扩展。遗传性疾病等位基因表达一种有毒蛋白质，进一步的体细胞扩张是否会增加毒性尚不清楚。我们创建了一个高清小鼠模型，可以解决遗传和体细胞扩张的影响。我们在此表明，抑制体细胞扩张可显着延迟遗传相同疾病长度等位基因的同窝小鼠的疾病发作。此外，药理学抑制剂 XJB-5-131 可以抑制重复轨迹的延长，并与这些动物运动衰退的挽救相关。结果证明，抵消疾病进展的药理学方法是可能的。亨廷顿病 (HD) 是由单个疾病长度等位基因的遗传引起的，该等位基因含有扩展的 CAG 重复序列，随着年龄的增长，该重复序列在体组织中继续扩展。遗传突变无法纠正，但如果体细胞扩张导致疾病，那么治疗方法是可能的。遗传性疾病等位基因表达一种有毒蛋白质，进一步的体细胞扩张是否会增加毒性尚不清楚。在这里，我们描述了亨廷顿氏舞蹈症的小鼠模型，该模型使我们能够将遗传基因的影响与生命期间发生的扩张分开。我们发现阻断该基因的持续扩增会导致症状出现延迟。这一结果为未来旨在缩短重复的治疗方法打开了大门。
Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible. Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. There is no correction for the inherited mutation, but if somatic expansion contributes to disease, then a therapeutic approach is possible. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. Here we describe a mouse model of Huntington’s disease that allows us to separate out the effects of the inherited gene from the expansion that occurs during life. We find that blocking the continued expansion of the gene causes a delay in onset of symptoms. This result opens the doors to future therapeutics designed to shorten the repeat.