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Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X
Sameer Aryal1,2, Francesco Longo2, Eric Klann3,4
1Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016.
Abstract:
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.
Insights
Loss of fragile X mental retardation protein (FMRP) causes altered protein synthesis in fragile X syndrome (FXS). Genetic reduction of p70 S6 kinase 1 (S6K1) normalizes translation and corrects FXS phenotypes.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Fragile X syndrome (FXS) results from loss of fragile X mental retardation protein (FMRP).
- FMRP's role in repressing protein synthesis and its translational targets are debated.
- Previous work indicated p70 S6 kinase 1 (S6K1) genetic removal corrects FXS phenotypes in mice.
Purpose of the Study:
- Investigate gene-specific mRNA translation alterations in FXS.
- Elucidate the mechanism by which S6K1 reduction rescues FXS-associated translational defects.
Main Methods:
- Utilized ribosome profiling and RNA sequencing on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice.
- Performed molecular assays to analyze ribosome translocation rates and translation efficiencies.
- Examined the relationship between coding sequence length and translation efficiency alterations.
Main Results:
- Observed reduced ribosome footprint (RF) abundance in most differentially translated genes in FXS mouse cortices.
- Found that reduced RF abundance correlates with increased ribosome translocation rates.
- Demonstrated that S6K1 genetic reduction normalizes RF abundance and prevents altered translation efficiency gradients in FXS mice.
Conclusions:
- Identified specific dysregulated mRNAs in FXS.
- Revealed that S6K1 reduction normalizes aberrant protein synthesis by increasing ribosome translocation.
- Established a molecular mechanism for S6K1's rescue effect in FXS, highlighting its therapeutic potential.
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