Dysregulation and restoration of translational homeostasis in fragile X syndrome

Key Points Fragile X syndrome (FXS) is an X-linked heritable form of intellectual disability with a high incidence of autism spectrum disorder (ASD) characteristics. FXS is recognized as the most commonly inherited form of intellectual disability and ASD. FXS is a CGG-repeat disease that causes silencing of the fragile X mental retardation 1 ( FMR1 ) gene and loss of its protein product, FMR protein (FMRP). FMRP is an mRNA-binding protein that mainly acts as a translational repressor. Excessive basal protein synthesis has been reported in FXS model mice that lack Fmr1 as well as in cells from individuals with FXS. Ten studies have reported genetic rescue of FXS pathophysiologies in Fmr1 -knockout mice. Eight of these genetic rescues normalize excessive protein synthesis in the FXS model mice, consistent with the hypothesis that resetting translational homeostasis is central to the rescue mechanisms. If resetting translational homeostasis is central to the rescue of FXS pathophysiologies, it suggests that there are specific mRNAs whose translation is elevated in FXS and normalized in the genetic rescues. These mRNAs are likely to have profound implications for the aetiology of FXS. Fragile X syndrome (FXS) results from the loss of the RNA-binding protein fragile X mental retardation protein (FMRP). Here, Klann and colleagues discuss the ways in which FMRP loss disrupts mRNA translation in the brain and the outcomes of genetic and pharmacological attempts to reset translational homeostasis in FXS model mice. Fragile X syndrome (FXS), the most-frequently inherited form of intellectual disability and the most-prevalent single-gene cause of autism, results from a lack of fragile X mental retardation protein (FMRP), an RNA-binding protein that acts, in most cases, to repress translation. Multiple pharmacological and genetic manipulations that target receptors, scaffolding proteins, kinases and translational control proteins can rescue neuronal morphology, synaptic function and behavioural phenotypes in FXS model mice, presumably by reducing excessive neuronal translation to normal levels. Such rescue strategies might also be explored in the future to identify the mRNAs that are critical for FXS pathophysiology.