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CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome
Science Advances ( IF 11.7 ) Pub Date : 2021-01-13 , DOI: 10.1126/sciadv.abd9440
Sefan Asamitsu 1 , Yasushi Yabuki 1, 2 , Susumu Ikenoshita 1, 3 , Kosuke Kawakubo 1, 2 , Moe Kawasaki 1, 2 , Shingo Usuki 4 , Yuji Nakayama 5 , Kaori Adachi 6 , Hiroyuki Kugoh 7, 8 , Kazuhiro Ishii 9 , Tohru Matsuura 10 , Eiji Nanba 11 , Hiroshi Sugiyama 12 , Kohji Fukunaga 13 , Norifumi Shioda 1, 2
Affiliation  

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in FMR1, which elicit repeat-associated non-AUG (RAN) translation and produce the toxic protein FMRpolyG. We show that FMRpolyG interacts with pathogenic CGG repeat-derived RNA G-quadruplexes (CGG-G4RNA), propagates cell to cell, and induces neuronal dysfunction. The FMRpolyG polyglycine domain has a prion-like property, preferentially binding to CGG-G4RNA. Treatment with 5-aminolevulinic acid, which is metabolized to protoporphyrin IX, inhibited RAN translation of FMRpolyG and CGG-G4RNA–induced FMRpolyG aggregation, ameliorating aberrant synaptic plasticity and behavior in FXTAS model mice. Thus, we present a novel therapeutic strategy to target G4RNA prionoids.



中文翻译:

CGG 重复 RNA G-四链体与 FMRpolyG 相互作用导致脆性 X 相关震颤/共济失调综合征的神经元功能障碍

脆性 X 相关震颤/共济失调综合征 (FXTAS) 是一种由FMR1中 CGG 三重重复扩增引起的神经退行性疾病,它引发重复相关的非 AUG (RAN) 翻译并产生有毒蛋白 FMRpolyG。我们显示 FMRpolyG 与致病性 CGG 重复衍生的 RNA G-四链体 (CGG-G4RNA) 相互作用,在细胞间传播,并诱导神经元功能障碍。FMRpolyG 多聚甘氨酸结构域具有类似朊病毒的特性,优先与 CGG-G4RNA 结合。用代谢为原卟啉 IX 的 5-氨基乙酰丙酸处理抑制 FMRpolyG 的 RAN 翻译和 CGG-G4RNA 诱导的 FMRpolyG 聚集,改善 FXTAS 模型小鼠的异常突触可塑性和行为。因此,我们提出了一种针对 G4RNA 朊病毒的新治疗策略。

更新日期:2021-01-14
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