Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease
Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease
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DOI：
10.1073/pnas.1221891110
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发表时间：
2013-02-05
影响因子：
11.1
通讯作者：
Bates, Gillian P.
中科院分区：
文献类型：
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作者：
Sathasivam, Kirupa;Neueder, Andreas;Bates, Gillian P.
亨廷顿病(HD)是一种毁灭性的、起病晚的遗传性神经退行性疾病，表现为个性改变、运动障碍和认知能力下降。它是由HTT基因外显子1上的CAG重复扩增引起的，该外显子翻译成亨廷顿蛋白(HTT)中的多谷氨酰胺途径。HTT片段的形成被认为是HD分子发病机制中的一个重要步骤，目前已鉴定出几种裂解HTT的蛋白酶。然而，更小的N-末端片段的重要性已经被它们在HD死后大脑中的存在以及核内含物只被HTT的N末端抗体检测到的事实所突显。尽管进行了密集的研究工作，但这些碎片的确切长度和产生机制仍不清楚。在这里，我们表明，CAG重复长度依赖于外显子1 HTT的异常剪接导致一个短的多腺苷化的mRNA，它被翻译成外显子1的HTT蛋白。鉴于突变的外显子1 HTT蛋白在HD小鼠模型中一直被证明是高致病性的，HTT mRNA的异常剪接为HD的分子发病机制提供了机制基础。针对RNA的治疗策略正在开发中，旨在降低HTT水平。这些方法中的许多方法都不能阻止外显子1 HTT的产生，应该根据我们的发现进行审查。
Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat length-dependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings.