Asamitsu Sefan, Yabuki Yasushi, Ikenoshita Susumu, Kawakubo Kosuke, Kawasaki Moe, Usuki Shingo, Nakayama Yuji, Adachi Kaori, Kugoh Hiroyuki, Ishii Kazuhiro, Matsuura Tohru, Nanba Eiji, Sugiyama Hiroshi, Fukunaga Kohji, Shioda Norifumi
Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan.
Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Sci Adv. 2021 Jan 13;7(3). doi: 10.1126/sciadv.abd9440. Print 2021 Jan.
Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in , 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.
脆性X相关震颤/共济失调综合征（FXTAS）是一种由基因中CGG三联体重复扩增引起的神经退行性疾病，这种扩增引发重复相关的非AUG（RAN）翻译并产生有毒蛋白FMRpolyG。我们发现FMRpolyG与致病性CGG重复序列衍生的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的聚甘氨酸结构域具有朊病毒样特性，优先结合CGG-G4RNA。5-氨基乙酰丙酸代谢生成原卟啉IX，用其治疗可抑制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类朊病毒的新型治疗策略。
