Elucidating Fragile X Syndrome by Investigating FMRP Molecular Function

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Fragile X Syndrome (FXS) is the most common inherited cause of intellectual impairment and most prevalent single gene cause of autism. Individuals afflicted with the disorder, 1 in ~4000 boys and 1 in ~7000 girls, present with a range of symptoms including speech and developmental delays, aggression, hyper-excitability, and perseveration. The disorder is the result of a triplet nucleotide repeat expansion and epigenetic silencing of the gene FMR1. Fmr1 knockout (KO) mice display pathophysiologies associated with the syndrome and thus serve as a model for therapeutic development. Many inchoate therapies focus on dys-regulated events downstream of FMRP activity, but few are concentrated on molecular mechanisms of FMRP function itself. FMRP binds specific mRNAs in the brain and does so primarily through interactions with coding regions. This observation plus the fact that it generally inhibits translation has led to the hypothesis that it normally stalls or slows ribosome translocation, thereby reducing polypeptide elongation. Several studies have now shown that indeed FMRP stalls ribosomes on specific mRNAs. Emerging evidence suggests that FMRP binds the ribosome, but the molecular mechanism of translational stalling remains an enigma. High-resolution structural analysis might indicate regions on the ribosome that are associated with FMRP, possibly leading to the development of small-molecule or other replacements that can be used to treat FXS. With that long-term goal in mind, we propose two specific aims to first identify regions in mRNA that are bound by FMRP-stalled ribosomes, and then to use such RNA regions to form FMRP-stalled ribosome complexes for cryo-EM structure determination. The FMRP-ribosome contact points would not only indicate a molecular mechanism of ribosome stalling, but would suggest potential therapeutic approaches that could mimic FMRP function to mitigate FXS.