RNA Related Pathology in Huntington's Disease.
RNA Related Pathology in Huntington's Disease.
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DOI：
10.1007/978-3-319-71779-1_4
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发表时间：
2018
影响因子：
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通讯作者：
Andreas Neueder;G. Bates
中科院分区：
文献类型：
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作者：
Andreas Neueder;G. Bates
本章总结了关于Huntingtin正义和反义转录本的表达、突变对Huntingtin加工的影响以及突变对编码和非编码转录本的更全局影响的研究。尽管亨廷顿蛋白基因的表达水平因组织和细胞类型的不同而不同，但其表达普遍存在。影响亨廷顿蛋白启动子中的NF-ĸB结合的单核苷酸多态性调节亨廷顿蛋白转录本的表达水平，并与疾病的发病年龄有关。研究表明，外显子1和外显子2之间的不完全剪接导致了编码高致病性外显子1亨廷顿蛋白的小片段多聚腺苷化的mRNA的表达。这在所有全长HD小鼠模型以及HD患者死后脑和成纤维细胞中以CAG重复长度依赖的方式发生。产生了一个亨廷顿蛋白的反义转录本，其中包含一个在HD患者中扩增的CUG重复序列。在强直性肌营养不良症中，扩大的CUG重复在细胞核内形成RNA焦点，结合特定的蛋白质(例如MBL1)。大约21个核苷酸的短的、纯的CAG RNA可以抑制其他含有mRNAs的CAG重复序列的翻译。HD突变在mRNA表达、剪接和非编码RNA的表达水平上影响转录组。最后，核苷酸的扩展重复延伸可以导致RAN翻译，其中核糖体从所有可能的阅读框架中的扩展重复翻译而来，产生具有各种多氨基酸链的蛋白质。这些事件在HD发病机制中的作用程度在很大程度上尚不清楚。
This chapter summarises research investigating the expression of huntingtin sense and anti-sense transcripts, the effect of the mutation on huntingtin processing as well as the more global effect of the mutation on the coding and non-coding transcriptomes. The huntingtin gene is ubiquitously expressed, although expression levels vary between tissues and cell types. A SNP that affects NF-ĸB binding in the huntingtin promoter modulates the expression level of huntingtin transcripts and is associated with the age of disease onset. Incomplete splicing between exon 1 and exon 2 has been shown to result in the expression of a small polyadenylated mRNA that encodes the highly pathogenic exon 1 huntingtin protein. This occurs in a CAG-repeat length dependent manner in all full-length mouse models of HD as well as HD patient post-mortem brains and fibroblasts. An antisense transcript to huntingtin is generated that contains a CUG repeat that is expanded in HD patients. In myotonic dystrophy, expanded CUG repeats form RNA foci in cell nuclei that bind specific proteins (e.g. MBL1). Short, pure CAG RNAs of approximately 21 nucleotides that have been processed by DICER can inhibit the translation of other CAG repeat containing mRNAs. The HD mutation affects the transcriptome at the level of mRNA expression, splicing and the expression of non-coding RNAs. Finally, expanded repetitive stretched of nucleotides can lead to RAN translation, in which the ribosome translates from the expanded repeat in all possible reading frames, producing proteins with various poly-amino acid tracts. The extent to which these events contribute to HD pathogenesis is largely unknown.