A Novel Function for Fragile X Mental Retardation Protein in Translational Activation

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Abstract
Fragile X syndrome, the most frequent form of inherited mental retardation, is due to the absence of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in several steps of RNA metabolism. To date, two RNA motifs have been found to mediate FMRP/RNA interaction, the G-quartet and the “kissing complex,” which both induce translational repression in the presence of FMRP. We show here a new role for FMRP as a positive modulator of translation. FMRP specifically binds Superoxide Dismutase 1 (Sod1) mRNA with high affinity through a novel RNA motif, SoSLIP (Sod1 mRNA Stem Loops Interacting with FMRP), which is folded as three independent stem-loop structures. FMRP induces a structural modification of the SoSLIP motif upon its interaction with it. SoSLIP also behaves as a translational activator whose action is potentiated by the interaction with FMRP. The absence of FMRP results in decreased expression of Sod1. Because it has been observed that brain metabolism of FMR1 null mice is more sensitive to oxidative stress, we propose that the deregulation of Sod1 expression may be at the basis of several traits of the physiopathology of the Fragile X syndrome, such as anxiety, sleep troubles, and autism. The most common form of inherited mental retardation, Fragile X syndrome, is caused by the absence of the Fragile X Mental Retardation Protein (FMRP), which can bind mRNA. In mice devoid of FMRP, several hundreds of mRNAs with altered expression and localization have been reported. The impact of these abnormalities is particularly important in the brain, where the absence of FMRP affects the structure and function of connections between neurons, resulting in reduced cognitive abilities. In recent years, scientists studying Fragile X syndrome have focused on identifying the RNAs that are specifically bound by FMRP. We and others have identified two specific RNA structures bound by FMRP/RNA. Importantly, when FMRP binds these structures, the translation of the RNA into its protein product is inhibited. In this new study we have identified a third FMRP-binding RNA structure that is found in the mRNA that encodes superoxide dismutase, an oxidative-stress-mitigating enzyme. Most significantly, FMRP enhances translation of the superoxide dismutase mRNA when it interacts with the structure. These findings suggest that absence of FMRP might result in reduced levels of superoxide dismutase, which in turn leads to increased oxidative stress in the brain. Interestingly, oxidative stress in the brain has already been linked to anxiety, sleeping difficulties, and autism, all of which typically affect individuals with Fragile X syndrome.