FMRP links optimal codons to mRNA stability in neurons
Huan Shu, Elisa Donnard, Botao Liu, Suna Jung, Ruijia Wang, Joel D. Richter
Abstract
Significance Fragile X syndrome (FXS), the most prevalent monogenic form of autism, is caused by the loss of FMRP, an RNA binding protein. In the absence of FMRP, translation is dysregulated, but restoration of translational homeostasis rescues the syndrome and thus could suggest new treatments for the disorder. Using ribosome profiling and RNA metabolic profiling, we show that, in the FMRP-deficient mouse brain, there are few specific translational disturbances. Instead, there is widespread imbalance of RNA levels. This imbalance is caused by destabilization of the FMRP targets and other mRNAs based on codon optimality. Rebalancing the transcriptome may therefore be a key to correcting syndrome-related pathophysiologies. This study establishes a role for FMRP in linking codon optimality to RNA stability.