气候变化领域集成服务门户(CCPortal): Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice

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DOI	10.1073/pnas.2001681118
	Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice
	Aryal S.; Longo F.; Klann E.
发表日期	2021
ISSN	00278424
卷号	118 期号:18
英文摘要	Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene specificity of altered messenger RNA (mRNA) translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA sequencing on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint (RF) abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in RF abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/ mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Autism; Fragile X syndrome; MRNA translation; Protein synthesis; Translation elongation
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179698
作者单位	Sackler Institute of Graduate Biomedical Sciences, New York University, School of Medicine, New York, NY 10016, United States; Center for Neural Science, New York University, New York, NY 10003, United States; New York University Langone Health's Neuroscience Institute, New York University, School of Medicine, New York, NY 10016, United States
推荐引用方式 GB/T 7714	Aryal S.,Longo F.,Klann E.. Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice[J],2021,118(18).
APA	Aryal S.,Longo F.,&Klann E..(2021).Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice.Proceedings of the National Academy of Sciences of the United States of America,118(18).
MLA	Aryal S.,et al."Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice".Proceedings of the National Academy of Sciences of the United States of America 118.18(2021).