当前位置: X-MOL 学术Nat. Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome.
Nature Medicine ( IF 58.7 ) Pub Date : 2018-Jun-01 , DOI: 10.1038/s41591-018-0018-6
Norifumi Shioda , Yasushi Yabuki , Kouya Yamaguchi , Misaki Onozato , Yue Li , Kenji Kurosawa , Hideyuki Tanabe , Nobuhiko Okamoto , Takumi Era , Hiroshi Sugiyama , Takahito Wada , Kohji Fukunaga

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.

中文翻译:

靶向G-四链体DNA作为ATR-X综合征的认知功能治疗。

α-地中海贫血X连锁型智力障碍(ATR-X)综合征是由ATRX突变引起的,该突变编码一种染色质重塑蛋白。小鼠和人类细胞中的全基因组分析表明,ATRX倾向于与富含G的序列结合,并具有形成G-四链体的高潜力。在这里,我们报告Atrx突变诱导Xlr3b在小鼠大脑中的表达异常上调,这与ATR-X模型小鼠显示的神经元发病机制有关。我们表明,ATRX通常会与印迹的Xlr3b基因的CpG岛中的G-四链体结合,通过募集DNA甲基转移酶来调节其表达。Xlr3b绑定到树突状mRNA,其过表达抑制编码CaMKII-α的mRNA的树突状转运,从而促进突触功能障碍。值得注意的是,用5-ALA治疗 被转化为G-四链体结合代谢产物的蛋白,可减少RNA聚合酶II的募集并抑制ATR-X模型小鼠的Xlr3b转录。5-ALA治疗还可以挽救ATR-X模型小鼠中突触可塑性和认知缺陷的降低。我们的发现表明靶向G-四链体并减少与ATR-X综合征相关的认知障碍的潜在治疗策略。
更新日期:2018-05-22
down
wechat
bug