FMRP activates the translation of large autism/intellectual disability proteins and stimulates N-end rule E3 ligase Poe/UBR4 production within puromycin-sensitive RNP particles

Abstract

Mutations in Fmr1 are the leading heritable cause of intellectual disability and autism spectrum disorder. We previously found that Fmr1 acts as a ~2-fold activator of translation of large proteins in Drosophila oocytes, in contrast to its proposed role as a repressor of translation elongation. Here, we show that genes associated with autism spectrum disorders tend to be dosage-sensitive and encode proteins that are larger than average. Reanalysis of Fmr1 KO mouse cortex ribosome profiling data demonstrates that autism-associated mRNAs encoding large proteins exhibit a concordant reduction in ribosome footprints, consistent with a general role for Fmr1 as a translational activator. We find no evidence that differential ribosomal pausing affects translational output in Fmr1-deficient Drosophila oocytes or mouse cortex. Furthermore, long Fmr1 target transcripts are preferentially enriched in stress granules upon acute stress. Our data thus identify a critical role for Fmr1 in promoting the translation of long, stress-sensitive, autism-associated mRNAs.

Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice

“…Earlier work has suggested that the coding sequence (CDS) length of an mRNA is associated with alterations in ribosome association in FXS. 47 – 50 To examine whether the CDS length of an mRNA dictates its ribosome association in dSPNs of FXS model mice, we ordered all mRNAs ascendingly by their CDS lengths, divided them into six color-coded bins, and evaluated their log2-fold changes (LFCs) against their FDR-adjusted p values. Consistent with the prior observations, mRNAs with the longest CDSs were enriched in genes with significantly reduced ribosome association in dSPNs of mice lacking FMRP, while those with the shortest CDSs were enriched in genes with significantly increased ribosome association ( Figure S4B ).…”

Cell type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behaviour in fragile X syndrome model mice

“…Earlier work has suggested that the coding sequence (CDS) length of an mRNA is associated with alterations in ribosome association in FXS 31,[45][46][47] . To examine whether the CDS length of an mRNA dictates its ribosome association in dSPNs of FXS model mice, we ordered all mRNAs ascendingly by their CDS lengths, divided them into six color-coded bins, and evaluated their log2-fold changes against their FDR-adjusted p-values.…”