Repeat-associated non-AUG-initiated translation of expanded CGG repeats (CGG RAN) from the FMR1 5'-leader produces toxic proteins that contribute to neurodegeneration in fragile X-associated tremor/ataxia syndrome. Here we describe how unexpanded CGG repeats and their translation play conserved roles in regulating fragile X protein (FMRP) synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production. Activation of mGluR5 receptors enhances FMRP synthesis. This enhancement requires both the CGG repeat and CGG RAN initiation sites. Using non-cleaving antisense oligonucleotides (ASOs), we selectively blocked CGG RAN. This ASO blockade enhanced endogenous FMRP expression in human neurons. In human and rodent neurons, CGG RAN-blocking ASOs suppressed repeat toxicity and prolonged survival. These findings delineate a native function for CGG repeats and RAN translation in regulating basal and activity-dependent FMRP synthesis, and they demonstrate the therapeutic potential of modulating CGG RAN translation in fragile X-associated disorders.

中文翻译：

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RAN翻译和CGG的天然功能在调节脆弱的X蛋白合成中具有重复性。

FMR1 5'-leader的扩展CGG重复序列（CGG RAN）的重​​复相关的非AUG起始翻译产生了有毒蛋白质，这些蛋白质在脆性X相关性震颤/共济失调综合征中导致神经退行性变。在这里，我们描述了未扩增的CGG重复序列及其翻译如何在调节脆性X蛋白（FMRP）合成中发挥保守作用。在神经元中，CGG RAN充当抑制上游开放阅读框，以抑制基础FMRP的产生。mGluR5受体的激活增强了FMRP的合成。这种增强需要CGG重复序列和CGG RAN起始位点。使用非裂解的反义寡核苷酸（ASO），我们选择性地阻断了CGG RAN。这种ASO阻断增强了人类神经元中内源性FMRP的表达。在人和啮齿动物神经元中，CGG RAN阻滞性ASO抑制重复毒性并延长生存期。