Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Cells. 2022 Apr 4;11(7):1223. doi: 10.3390/cells11071223.
RNA toxicity contributes to diseases caused by anomalous nucleotide repeat expansions. Recent work demonstrated RNA-based toxicity from repeat-associated, non-AUG-initiated translation (RAN translation). RAN translation occurs around long nucleotide repeats that form hairpin loops, allowing for translation initiation in the absence of a start codon that results in potentially toxic, poly-amino acid repeat-containing proteins. Discovered in Spinocerebellar Ataxia Type (SCA) 8, RAN translation has been documented in several repeat-expansion diseases, including in the CAG repeat-dependent polyglutamine (polyQ) disorders. The ATXN3 gene, which causes SCA3, also known as Machado-Joseph Disease (MJD), contains a CAG repeat that is expanded in disease. ATXN3 mRNA possesses features linked to RAN translation. In this paper, we examined the potential contribution of RAN translation to SCA3/MJD in by using isogenic lines that contain homomeric or interrupted CAG repeats. We did not observe unconventional translation in fly neurons or glia. However, our investigations indicate differential toxicity from ATXN3 protein-encoding mRNA that contains pure versus interrupted CAG repeats. Additional work suggests that this difference may be due in part to toxicity from homomeric CAG mRNA. We conclude that is not suitable to model RAN translation for SCA3/MJD, but offers clues into the potential pathogenesis stemming from CAG repeat-containing mRNA in this disorder.
RNA 毒性导致异常核苷酸重复扩展引起的疾病。最近的工作表明，重复相关的非 AUG 起始翻译（RAN 翻译）会产生基于 RNA 的毒性。RAN 翻译发生在形成发夹环的长核苷酸重复周围，允许在没有起始密码子的情况下进行翻译起始，从而导致潜在毒性的、多氨基酸重复的蛋白质。在脊髓小脑共济失调 8 型（SCA8）中发现的 RAN 翻译已在几种重复扩展疾病中得到证实，包括 CAG 重复依赖性多聚谷氨酰胺（polyQ）疾病。导致 SCA3（也称为 Machado-Joseph 病，MJD）的 ATXN3 基因含有一个在疾病中扩展的 CAG 重复。ATXN3 mRNA 具有与 RAN 翻译相关的特征。在本文中，我们通过使用含有同型或中断的 CAG 重复的同基因系，研究了 RAN 翻译对 SCA3/MJD 的潜在贡献。我们在果蝇神经元或神经胶质中未观察到非常规翻译。然而，我们的研究表明，含有纯 CAG 重复或中断 CAG 重复的 ATXN3 蛋白编码 mRNA 存在差异毒性。进一步的工作表明，这种差异可能部分归因于同型 CAG mRNA 的毒性。我们得出结论， 不适于作为 SCA3/MJD 的 RAN 翻译模型，但为该疾病中 CAG 重复 mRNA 引起的潜在发病机制提供了线索。
