دورية أكاديمية
Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice.
| العنوان: | Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice. |
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| المؤلفون: | Aryal S; Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016.; Center for Neural Science, New York University, New York, NY 10003., Longo F; Center for Neural Science, New York University, New York, NY 10003., Klann E; Center for Neural Science, New York University, New York, NY 10003; eklann@cns.nyu.edu.; New York University Langone Health's Neuroscience Institute, New York University School of Medicine, New York, NY 10016. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 May 04; Vol. 118 (18). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Protein Biosynthesis*, Fragile X Mental Retardation Protein/*genetics , Fragile X Syndrome/*genetics , Ribosomal Protein S6 Kinases, 70-kDa/*genetics, Animals ; Dendritic Spines/genetics ; Dendritic Spines/pathology ; Disease Models, Animal ; Fragile X Syndrome/pathology ; Fragile X Syndrome/therapy ; Humans ; Mice ; Mice, Knockout ; Mutation/genetics ; Neurons/metabolism ; Neurons/pathology ; Open Reading Frames/genetics ; RNA, Messenger/genetics |
| مستخلص: | 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. Competing Interests: The authors declare no competing interest. |
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| معلومات مُعتمدة: | P30 CA016087 United States CA NCI NIH HHS; R01 NS034007 United States NS NINDS NIH HHS; R01 NS047384 United States NS NINDS NIH HHS; R37 NS034007 United States NS NINDS NIH HHS; U54 HD082013 United States HD NICHD NIH HHS; R29 NS034007 United States NS NINDS NIH HHS |
| فهرسة مساهمة: | Keywords: autism; fragile X syndrome; mRNA translation; protein synthesis; translation elongation |
| المشرفين على المادة: | 0 (Fmr1 protein, mouse) 0 (RNA, Messenger) 139135-51-6 (Fragile X Mental Retardation Protein) EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) |
| تواريخ الأحداث: | Date Created: 20210428 Date Completed: 20211203 Latest Revision: 20211214 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8106352 |
| DOI: | 10.1073/pnas.2001681118 |
| PMID: | 33906942 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.2001681118 |