FMRP Regulates Neuronal RNA Granules Containing Stalled Ribosomes, Not Where Ribosomes Stall

Ribosomes stalled at elongation make up a sizable percentage of mRNAs translated in developing neurons. The protein lost in Fragile X syndrome (FMRP) is highly enriched in RNA granules containing stalled ribosomes, both of which play crucial roles in regulating forms of synaptic plasticity such as metabotropic glutamate receptor-dependent long-term depression (mGLUR-LTD).

Previous examination of ribosome protected fragments (RPFs) from neuronal stalled ribosomes have identified motifs matching those found in mRNAs associated with FMRP, as recognized by FMRP cross-linking immunoprecipitation (CLIP) (Anadolu et al., 2023, Journal of Neuroscience doi: 10.1523/JNEUROSCI.1002-22.2023). To investigate if FMRP recognition of these sequences is important for determining where mRNAs are stalled, we examined stalled ribosomes RPFs isolated from P5 mice lacking the FMRP protein.