Loss of the fragile X syndrome protein FMRP results in misregulation of nonsense-mediated mRNA decay

Maquat and colleagues report that nonsense-mediated mRNA decay is activated upon loss of the fragile X syndrome protein FMRP in patient-derived induced pluripotent stem cells, which results in defects in neuronal differentiation. Loss of the fragile X protein FMRP is a leading cause of intellectual disability and autism(1,2), but the underlying mechanism remains poorly understood. We report that FMRP deficiency results in hyperactivated nonsense-mediated mRNA decay (NMD)(3,4) in human SH-SY5Y neuroblastoma cells and fragile X syndrome (FXS) fibroblast-derived induced pluripotent stem cells (iPSCs). We examined the underlying mechanism and found that the key NMD factor UPF1 binds directly to FMRP, promoting FMRP binding to NMD targets. Our data indicate that FMRP acts as an NMD repressor. In the absence of FMRP, NMD targets are relieved from FMRP-mediated translational repression so that their half-lives are decreased and, for those NMD targets encoding NMD factors, increased translation produces abnormally high factor levels despite their hyperactivated NMD. Transcriptome-wide alterations caused by NMD hyperactivation have a role in the FXS phenotype. Consistent with this, small-molecule-mediated inhibition of hyperactivated NMD, which typifies iPSCs derived from patients with FXS, restores a number of neurodifferentiation markers, including those not deriving from NMD targets. Our mechanistic studies reveal that many molecular abnormalities in FMRP-deficient cells are attributable-either directly or indirectly-to misregulated NMD.

Automated summary

The loss of fragile X syndrome protein FMRP leads to hyperactivated nonsense-mediated mRNA decay, resulting in defects in neuronal differentiation. The key NMD factor UPF1 directly binds to FMRP, promoting abnormal translation of NMD targets and contributing to molecular abnormalities in FMRP-deficient cells. Inhibition of hyperactivated NMD restores neurodifferentiation markers in FXS patient-derived iPSCs.