美国密歇根大学Peter K. Todd课题组发现CGG重复序列及其翻译在调节脆性X蛋白（FMRP）合成过程中的天然功能。该项研究成果在线发表在2020年2月17日的《自然—神经科学》上。

研究描述了未扩增的CGG 重复序列及其翻译如何在FMRP合成中发挥保守作用。在神经元中，FMR1 5'-leader的扩展CGG重复序列相关的非AUG起始翻（CGG RAN）能够抑制上游开放阅读框，以抑制基础FMRP的产生。mGluR5受体的激活促进了FMRP的合成。这种促进作用需要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），他们选择性地阻断CGG RAN。这种CGG RAN阻断促进了人类神经元中内源性FMRP的表达。在人类和啮齿动物神经元中，CGG RAN阻断的ASO抑制重复毒性并延长生存期。这些发现表明CGG重复序列和RAN翻译在调节基础和活动依赖性FMRP合成中的天然功能，他们证明了在脆性X相关疾病中调节CGG RAN翻译的治疗潜力。

研究人员表示，CGG RAN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病变。

附：英文原文

Title: A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis

Author: Caitlin M. Rodriguez, Shannon E. Wright, Michael G. Kearse, Jill M. Haenfler, Brittany N. Flores, Yu Liu, Marius F. Ifrim, Mary R. Glineburg, Amy Krans, Paymaan Jafar-Nejad, Michael A. Sutton, Gary J. Bassell, Jack M. Parent, Frank Rigo, Sami J. Barmada, Peter K. Todd

Issue&Volume: 2020-02-17

Abstract: 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.

DOI: 10.1038/s41593-020-0590-1

Source: https://www.nature.com/articles/s41593-020-0590-1