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J.C. Darnell et al., “FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism,”Cell, 146:247-61, 2011. Free F1000 Evaluation
Fragile X syndrome, which is associated with autistic behavior, is almost always caused by loss of the protein FMRP. Although researchers knew that FMRP binds polyribosomes and mRNA to regulate synaptic plasticity, the mechanism was unknown. Robert Darnell at Rockefeller University and colleagues showed that FMRP regulates protein synthesis by reversibly stalling translation in neurons.
Darnell’s team started by identifying the mRNAs that FMRP binds. They zapped cells with UV to covalently bind FMRP and any mRNAs in direct contact and sequenced more than 800 of the bound mRNA transcripts. They noticed that FMRP-bound RNAs were also bound to ribosome complexes, which usually indicates active protein translation. But when the researchers forced ribosomes to finish translating and release their mRNA, those associated with FMRP stayed on. Protein synthesis was only restored when FMRP was coaxed away with decoy RNA strands, suggesting that it actively stalls translation.
The take home message
This “technically beautiful and complete” work demonstrates how FMRP regulates protein synthesis, says Dieter Wolf at Sanford-Burnam Medical Research Institute in La Jolla.
Although researchers now have a new pool of FMRP targets to begin investigating in detail, first author Jennifer Darnell does not think that overexpression of any one protein can cause Fragile X syndrome. Her lab is working to design therapeutic molecules that mimic FMRP’s action.