Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou 510632, China;
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4411-4417. doi: 10.1073/pnas.1919197117. Epub 2020 Feb 6.
Identification of repeat-associated non-AUG (RAN) translation in trinucleotide (CAG) repeat diseases has led to the emerging concept that CAG repeat diseases are caused by nonpolyglutamine products. Nonetheless, the in vivo contribution of RAN translation to the pathogenesis of CAG repeat diseases remains elusive. Via CRISPR/Cas9-mediated genome editing, we established knock-in mouse models that harbor expanded CAG repeats in the mouse gene to express RAN-translated products with or without polyglutamine peptides. We found that RAN translation is not detected in the knock-in mouse models when expanded CAG repeats are expressed at the endogenous level. Consistently, the expanded CAG repeats that cannot be translated into polyglutamine repeats do not yield the neuropathological and behavioral phenotypes that were found in knock-in mice expressing expanded polyglutamine repeats. Our findings suggest that RAN-translated products do not play a major role in the pathogenesis of CAG repeat diseases and underscore the importance in targeting polyglutamine repeats for therapeutics.
三核苷酸（CAG）重复疾病中重复相关的非 AUG（RAN）翻译的鉴定导致了一个新的概念，即 CAG 重复疾病是由非多谷氨酰胺产物引起的。尽管如此，RAN 翻译对 CAG 重复疾病发病机制的体内贡献仍然难以捉摸。通过 CRISPR/Cas9 介导的基因组编辑，我们建立了携带小鼠基因中扩增的 CAG 重复的基因敲入小鼠模型，以表达具有或不具有多谷氨酰胺肽的 RAN 翻译产物。我们发现，当扩增的 CAG 重复以内源性水平表达时，在基因敲入小鼠模型中未检测到 RAN 翻译。一致地，不能翻译为多谷氨酰胺重复的扩增的 CAG 重复不会产生在表达扩增的多谷氨酰胺重复的基因敲入小鼠中发现的神经病理学和行为表型。我们的研究结果表明，RAN 翻译产物在 CAG 重复疾病的发病机制中不起主要作用，并强调了针对多谷氨酰胺重复进行治疗的重要性。
