Kearse Michael G, Todd Peter K
Department of Neurology, University of Michigan Medical School, 4005 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.
Neurotherapeutics. 2014 Oct;11(4):721-31. doi: 10.1007/s13311-014-0292-z.
Nucleotide repeat expansions underlie numerous human neurological disorders. Repeats can trigger toxicity through multiple pathogenic mechanisms, including RNA gain-of-function, protein gain-of-function, and protein loss-of-function pathways. Traditionally, inference of the underlying pathogenic mechanism derives from the repeat location, with dominantly inherited repeats within transcribed noncoding sequences eliciting toxicity predominantly as RNA via sequestration of specific RNA binding proteins. However, recent findings question this assumption and suggest that repeats outside of annotated open reading frames may also trigger toxicity through a novel form of protein translational initiation known as repeat-associated non-AUG (RAN) translation. To date, RAN translation has been implicated in 4 nucleotide repeat expansion disorders: spinocerebellar ataxia type 8; myotonic dystrophy type 1 with CTG•CAG repeats; C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia with GGGGCC•GGCCCC repeats; and fragile X-associated tremor/ataxia syndrome with CGG repeats. RAN translation contributes to hallmark pathological characteristics in these disorders by producing homopolymeric or dipeptide repeat proteins. Here, we review what is known about RAN translation, with an emphasis on how differences in both repeat sequence and context may confer different requirements for unconventional initiation. We then discuss how this new mechanism of translational initiation might function in normal physiology and lay out a roadmap for addressing the numerous questions that remain.
核苷酸重复扩增是多种人类神经疾病的基础。重复序列可通过多种致病机制引发毒性，包括RNA功能获得、蛋白质功能获得和蛋白质功能丧失途径。传统上，潜在致病机制的推断源于重复序列的位置，转录非编码序列中的显性遗传重复序列主要通过隔离特定RNA结合蛋白以RNA形式引发毒性。然而，最近的研究结果对这一假设提出了质疑，并表明注释开放阅读框之外的重复序列也可能通过一种称为重复相关非AUG（RAN）翻译的新型蛋白质翻译起始形式引发毒性。迄今为止，RAN翻译已涉及4种核苷酸重复扩增疾病：8型脊髓小脑共济失调；伴有CTG•CAG重复序列的1型强直性肌营养不良；伴有GGGGCC•GGCCCC重复序列的C9orf72肌萎缩侧索硬化/额颞叶痴呆；以及伴有CGG重复序列的脆性X相关震颤/共济失调综合征。RAN翻译通过产生同聚物或二肽重复蛋白，导致这些疾病的标志性病理特征。在这里，我们综述了关于RAN翻译的已知信息，重点是重复序列和背景的差异如何可能对非常规起始产生不同要求。然后，我们讨论了这种新的翻译起始机制在正常生理学中可能如何发挥作用，并为解决众多遗留问题制定了路线图。
