The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington's disease patients.
The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington's disease patients.
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DOI：
10.1038/s41598-017-01510-z
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发表时间：
2017-05-02
影响因子：
4.6
通讯作者：
Bates GP
中科院分区：
文献类型：
--
作者：
Neueder A;Landles C;Ghosh R;Howland D;Myers RH;Faull RLM;Tabrizi SJ;Bates GP
我们以前已经表明，亨廷顿蛋白基因的外显子1并不总是剪接到外显子2，从而产生编码高致病性外显子1 HTT蛋白的小聚腺苷酸化mRNA（HTTexon1）。该通读产物的水平与CAG重复长度成比例，并且存在于CAG长度为50及以上的所有亨廷顿病（HD）敲入小鼠模型以及YAC 128和BACHD小鼠模型中，这两种小鼠模型均表达人HTT基因的拷贝。我们现在已经开发了特定的协议，用于定量分析人类组织中HTTexon 1的转录水平，并将其应用于一系列成纤维细胞系和成年发病或青少年发病HD个体的死后脑样本。我们发现HTTexon1 mRNA存在于青少年HD患者的成纤维细胞中，并且也可以在HD个体的死后大脑的感觉运动皮层、海马和小脑中容易地检测到，特别是在那些早发性疾病中。这一发现将对降低患者突变HTT水平的策略和未来治疗方法的设计产生重要影响。
We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington’s disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD. We found that the HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and can also be readily detected in the sensory motor cortex, hippocampus and cerebellum of post-mortem brains from HD individuals, particularly in those with early onset disease. This finding will have important implications for strategies to lower mutant HTT levels in patients and the design of future therapeutics.