Nat. Comm. 13, 3236 (2022)
Loss of expression of the mRNA-binding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene, causes fragile X syndrome (FXS), the most common inherited form of intellectual disability. A large body of work has demonstrated increased protein synthesis and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression (mGluR-LTD) in FXS model (Fmr1−/y) mice, but the mechanisms that underlie these observations and how they contribute to the pathology of FXS have remained unclear. Using proteomics and TRAP-seq (translating ribosome affinity purification with sequencing) to examine ribosome-bound mRNA, Seo, Louros et al. observed upregulation of ribosomal genes in hippocampal CA1 synapses from Fmr1−/y mice and provided evidence for elevated ribosome levels in Fmr1−/y neurons. Consistent with earlier studies showing that increased ribosome availability favors the translation of short mRNAs, the authors found that Fmr1−/y mice had higher levels of translation of short mRNAs, which are enriched for house-keeping genes, and decreased translation of long mRNAs, which are enriched for synaptic genes and autism risk genes. Induction of mGluR-LTD in wild-type brain slices increased ribosomal-protein translation and recapitulated the length imbalance of translating mRNAs, and these effects of mGluR-LTD were occluded in slices from Fmr1−/y mice and could be blocked by selectively inhibiting the transcription of ribosomal RNA. Thus, the authors provide a mechanistic link between altered translation and aberrant synaptic plasticity in a model of FXS.
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