| First Author | Zou Z | Year | 2023 |
| Journal | Mol Cell | Volume | 83 |
| Issue | 23 | Pages | 4304-4317.e8 |
| PubMed ID | 37949069 | Mgi Jnum | J:343572 |
| Mgi Id | MGI:7565226 | Doi | 10.1016/j.molcel.2023.10.028 |
| Citation | Zou Z, et al. (2023) FMRP phosphorylation modulates neuronal translation through YTHDF1. Mol Cell 83(23):4304-4317.e8 |
| abstractText | RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition. |
