CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome,Science Advances

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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

Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan.
Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Liaison Laboratory Research Promotion Center, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan.
Division of Radioisotope Science, Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, Tottori, Japan.
Division of Genomic Science, Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, Tottori, Japan.
Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Tottori, Japan.
Chromosome Engineering Research Center, Tottori University, Tottori, Japan.
Department of the Neurology, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
Division of Neurology, Department of Medicine, Jichi Medical University, Shimono, Japan.
Office for Research Strategy, Organization for Research Initiative and Promotion, Tottori University, Tottori, Japan.
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

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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