CGG repeat expansions in the FMR1 5’UTR cause the neurodegenerative disease Fragile X-associated tremor/ataxia syndrome (FXTAS). These repeats form stable RNA secondary structures that support aberrant translation in the absence of an AUG start codon (RAN translation), producing aggregate-prone peptides that accumulate within intranuclear neuronal inclusions and contribute to neurotoxicity. Here, we show that the most abundant RAN translation product, FMRpolyG, is markedly less toxic when generated from a construct with a non-repetitive alternating codon sequence in place of the CGG repeat. While exploring the mechanism of this differential toxicity, we observed a +1 translational frameshift within the CGG repeat from the arginine to glycine reading frame. Frameshifts occurred within the first few translated repeats and were triggered predominantly by RNA sequence and structural features. Short chimeric R/G peptides form aggregates distinct from those formed by either pure arginine or glycine, and these chimeras induce toxicity in cultured rodent neurons. Together, this work suggests that CGG repeats support translational frameshifting and that chimeric RAN translated peptides may contribute to CGG repeat-associated toxicity in FXTAS and related disorders.

中文翻译：

---

CGG 重复触发翻译移码，产生易于聚集的嵌合蛋白

FMR1 5'UTR 中的 CGG 重复扩展导致神经退行性疾病脆性 X 相关震颤/共济失调综合征 (FXTAS)。这些重复序列形成稳定的 RNA 二级结构，在没有 AUG 起始密码子（RAN 翻译）的情况下支持异常翻译，产生聚集倾向的肽，这些肽在核内神经元包涵体中积累并导致神经毒性。在这里，我们展示了最丰富的 RAN 翻译产物 FMRpolyG 在由具有非重复交替密码子序列代替 CGG 重复序列的构建体生成时毒性显着降低。在探索这种差异毒性的机制时，我们观察到 CGG 重复中从精氨酸到甘氨酸阅读框的 +1 翻译移码。移码发生在最初的几个翻译重复中，主要由 RNA 序列和结构特征触发。短嵌合 R/G 肽形成的聚集体不同于纯精氨酸或甘氨酸形成的聚集体，这些嵌合体在培养的啮齿动物神经元中诱导毒性。总之，这项工作表明 CGG 重复序列支持翻译移码，嵌合 RAN 翻译肽可能导致 FXTAS 和相关疾病中的 CGG 重复序列相关毒性。