The mechanisms of Fragile X syndrome
FXS is an inherited mental retardation condition that affects boys. It is caused by a mutation in the fragile X mental retardation gene (FMR1), which affects neuronal dendritic spines and the formation and function of synapses. The fragile X mental retardation protein (FMRP) is an RNA binding protein that regulates the transport, stability and translation of neuronal mRNAs. Deregulation of this process probably underlies the molecular aetiology of FXS. To elucidate the molecular mechanisms of FXS, scientists on the EU-funded SYNAPSES FXS project focused on neuronal synapses and the identification of affected molecules. To achieve this, they used different transgenic mouse models, including the mouse equivalent of FXS that carries a mutation in the FMR1 gene. They isolated the proteome of the postsynaptic membranes from the mouse hippocampus and cortex and are in the process of comparing it with normal synapses. This will unveil the molecular signalling networks that get dysregulated in FXS. So far, genome-wide association studies have disclosed a number of FMRP mRNA targets associated with autism, FXS and other neurological diseases. Further analyses of FXS synapses identified an altered profile of microRNA expression, clearly underscoring the importance of gene regulation in synapses lacking FMRP. From a regulatory perspective, the consortium addressed the mechanism of FMRP-mediated regulation of the PSD-95 and Arc targets. They discovered that another protein, FXRP2, interacts with FMRP to mediate repression or activation of these targets. Taken together, the findings of the SYNAPSES FXS study provide fundamental insight into the molecular events that take place in FXS. The identified molecules constitute targets for potential therapeutic exploitation, thereby facilitating amelioration of disease progression.
