Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice

Proc Natl Acad Sci U S A. 2021 May 4;118(18):e2001681118. doi: 10.1073/pnas.2001681118.

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.

Keywords: autism; fragile X syndrome; mRNA translation; protein synthesis; translation elongation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dendritic Spines / genetics
  • Dendritic Spines / pathology
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / pathology
  • Fragile X Syndrome / therapy
  • Humans
  • Mice
  • Mice, Knockout
  • Mutation / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Open Reading Frames / genetics
  • Protein Biosynthesis*
  • RNA, Messenger / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics*

Substances

  • Fmr1 protein, mouse
  • RNA, Messenger
  • Fragile X Mental Retardation Protein
  • Ribosomal Protein S6 Kinases, 70-kDa