Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders.
Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders.
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DOI：
10.1042/bst20200690
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发表时间：
2021-04-30
影响因子：
3.9
通讯作者：
Hautbergue GM
中科院分区：
文献类型：
--
作者：
Castelli LM;Huang WP;Lin YH;Chang KY;Hautbergue GM
2011年在脊髓小脑共济失调8型（SCA8）和强直性肌营养不良1型（DM1）中发现了重复相关的非AUG（RAN）翻译。这种非规范形式的翻译发生在来自携带三核苷酸至六核苷酸重复序列扩展的有义和反义转录物的编码区和非编码区的所有阅读框中。在53种已知的微卫星扩增疾病中，有7种主要表现为神经退行性特征，其中7种报告了RAN翻译。RAN翻译导致具有聚集和细胞毒性特性的低复杂性聚合重复蛋白的生物合成。然而，在没有典型AUG起始密码子的情况下，组装功能性核糖体所涉及的分子机制和蛋白质因素仍然很难表征，而二级重复RNA结构在启动RAN翻译中起关键作用。在这里，我们简要回顾了重复扩展障碍、其复杂的发病机制和生理翻译起始机制以及参与RAN翻译的已知因素。最后，我们讨论了研究的挑战，周围的发病机制和未来的方向，可能提供机会，为这组无法治愈的神经退行性疾病的新的治疗方法的发展的理解。
Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.