RNA toxicity induced by expanded CAG repeats in Huntington's disease
RNA toxicity induced by expanded CAG repeats in Huntington's disease
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DOI：
10.1111/bpa.12427
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发表时间：
2016-11-01
期刊：
影响因子：
6.4
通讯作者：
Marti, Eulalia
中科院分区：
文献类型：
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作者：
Marti, Eulalia
亨廷顿氏病（HD）属于遗传性多聚谷氨酰胺（PolyQ）疾病的组，其由亨廷顿蛋白（HTT）基因的编码区中的扩增的CAG重复引起，其导致延长的polyQ延伸。突变蛋白的异常功能和聚集通常被描述为疾病发展的主要分子原因。然而，最近的进展已经揭示了直接依赖于RNA毒性功能获得的新的致病途径。HTT mRNA外显子1内扩增的CAG重复序列通过涉及至少部分基因表达扰动的机制诱导毒性。这不仅对HD的基础和转化研究具有重要意义，而且对在其他基因中携带扩展CAG的其他类型的疾病也具有重要意义，这些疾病可能具有共同的致病性。在这里，我将审查CAG重复扩增的RNA毒性的证据和机制，特别是侧重于HD。这些包括含有扩增的CAG重复序列的转录物的异常亚细胞定位;扩增的CAG重复序列对几种类型的蛋白质的隔离，这导致可变剪接事件和基因表达的缺陷;以及产生改变的基因沉默的小CAG重复RNA（sCAG）的异常生物发生和有害活性。虽然这些改变的途径已在HD模型中检测到，但其对疾病发展和进展的贡献需要进一步研究。
Huntington's disease (HD) belongs to the group of inherited polyglutamine (PolyQ) diseases caused by an expanded CAG repeat in the coding region of the Huntingtin (HTT) gene that results in an elongated polyQ stretch. Abnormal function and aggregation of the mutant protein has been typically delineated as the main molecular cause underlying disease development. However, the most recent advances have revealed novel pathogenic pathways directly dependent on an RNA toxic gain-of-function. Expanded CAG repeats within exon 1 of the HTT mRNA induce toxicity through mechanisms involving, at least in part, gene expression perturbations. This has important implications not only for basic and translational research in HD, but also for other types of diseases carrying the expanded CAG in other genes, which likely share pathogenic aspects. Here I will review the evidence and mechanisms underlying RNA toxicity in CAG repeat expansions, with particular focus on HD. These comprise abnormal subcellular localization of the transcripts containing the expanded CAG repeats; sequestration of several types of proteins by the expanded CAG repeat which results in defects of alternative splicing events and gene expression; and aberrant biogenesis and detrimental activity of small CAG repeated RNAs (sCAG) that produce altered gene silencing. Although these altered pathways have been detected in HD models, their contribution to disease development and progress requires further study.