Abstract：
Expanded short tandem repeats in the genome cause various monogenic diseases, particularly neurological disorders. Since the discovery of a CGG repeat expansion in the FMR1 gene in 1991, more than 40 repeat expansion diseases have been identified to date. In the coding repeat expansion diseases, in which the expanded repeat sequence is located in the coding regions of genes, the toxicity of repeat polypeptides, particularly misfolding and aggregation of proteins containing an expanded polyglutamine tract, have been the focus of investigation. On the other hand, in the non-coding repeat expansion diseases, in which the expanded repeat sequence is located in introns or untranslated regions, the toxicity of repeat RNAs has been the focus of investigation. Recently, these repeat RNAs were demonstrated to be translated into repeat polypeptides by the novel mechanism of repeat-associated non-AUG translation, which has extended the research direction of the pathological mechanisms of this disease entity to include polypeptide toxicity. Thus, a common pathogenesis has been suggested for both coding and non-coding repeat expansion diseases. In this review, we briefly outline the major pathogenic mechanisms of repeat expansion diseases, including a loss-of-function mechanism caused by repeat expansion, repeat RNA toxicity caused by RNA foci formation and protein sequestration, and toxicity by repeat polypeptides. We also discuss perturbation of the physiological liquid-liquid phase separation state caused by these repeat RNAs and repeat polypeptides, as well as potential therapeutic approaches against repeat expansion diseases.
摘要：
基因组中扩展的短串联重复序列会导致各种单基因疾病，特别是神经系统疾病。自1991年在FMR1基因中发现CGG重复扩增以来,至今已鉴定出超过40种重复扩增疾病。在编码重复扩张疾病中，其中扩展的重复序列位于基因的编码区，重复多肽的毒性，特别是包含扩展的聚谷氨酰胺束的蛋白质的错误折叠和聚集，一直是调查的重点。另一方面,在非编码重复扩张疾病中，其中扩增的重复序列位于内含子或非翻译区，重复RNA的毒性一直是研究的焦点。最近,这些重复RNA被证明通过重复相关的非AUG翻译的新机制翻译成重复多肽，这将该疾病实体的病理机制的研究方向扩展到包括多肽毒性。因此，编码和非编码重复扩增疾病都有共同的发病机制.在这次审查中,我们简要概述了重复扩张疾病的主要致病机制，包括由重复扩张引起的功能丧失机制，由RNA病灶形成和蛋白质螯合引起的重复RNA毒性，和重复多肽的毒性。我们还讨论了由这些重复RNA和重复多肽引起的生理液-液相分离状态的扰动，以及针对重复扩张疾病的潜在治疗方法。
