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Post-translational modifications of the Fragile X Mental Retardation Protein in neuronal function and dysfunction

Abstract : The Fragile X Mental Retardation Protein (FMRP) is an RNA-binding protein essential to the regulation of local translation at synapses. In the mammalian brain, synapses are constantly formed and eliminated throughout development to achieve functional neuronal networks. At the molecular level, thousands of proteins cooperate to accomplish efficient neuronal communication. Therefore, synaptic protein levels and their functional interactions need to be tightly regulated. FMRP generally acts as a translational repressor of its mRNA targets. FMRP is the target of several post-translational modifications (PTMs) that dynamically regulate its function. Here we provide an overview of the PTMs controlling the FMRP function and discuss how their spatiotemporal interplay contributes to the physiological regulation of FMRP. Importantly, FMRP loss-of-function leads to Fragile X syndrome (FXS), a rare genetic developmental condition causing a range of neurological alterations including intellectual disability (ID), learning and memory impairments, autistic-like features and seizures. Here, we also explore the possibility that recently reported missense mutations in the FMR1 gene disrupt the PTM homoeostasis of FMRP, thus participating in the aetiology of FXS. This suggests that the pharmacological targeting of PTMs may be a promising strategy to develop innovative therapies for patients carrying such missense mutations.
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Submitted on : Friday, January 17, 2020 - 11:53:42 AM
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Marta Prieto, Alessandra Folci, Stéphane Martin. Post-translational modifications of the Fragile X Mental Retardation Protein in neuronal function and dysfunction. Molecular Psychiatry, Nature Publishing Group, In press, ⟨10.1038/s41380-019-0629-4⟩. ⟨inserm-02443603⟩

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