Window into brain what it tells us

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Fragile X syndrome is the most frequent cause of inherited mental retardation, caused by transcriptional silencing of the fragile X mental retardation gene, FMR1. In most cases, fragile X syndrome is caused by the expansion of a polymorphic CGG repeat in the 5′ untranslated region (UTR) of the gene. It is an X linked disorder, which is more common in boys, as they have only one X chromosome, a single fragile X is likely to affect them more severely. It was first discovered in 1943 by the scientists Martin and Bell that a kind of mental retardation was linked by the X chromosome. In 1970's, Sutherland, Dakar, and Harrison did independent cytogenetic studies on human X chromosome using electron microscopes suggesting that the heritable fragile sites were responsible for mental retardation [1].

As there were restrictions on the molecular front back in the eighties, the gene responsible for fragile X syndrome could not be cloned. Although, a great deal of both genetic and physical mapping was done. The geneticists were unsure about the syndrome being caused by the fragile site itself or a closely linked causal mutation, which was then clarified by the studies made by Vincent and Bell using markers for the fragile site [2]. In 1991, Verkerk showed that Fragile X syndrome is associated with a fragile site at Xg27.3. He suggested the involvement of FMR-1 gene in the phenotypic expression of the fragile X syndrome. At the molecular level, the fragile site is caused by a CGG triplet expansion (dynamic mutation) to more than 200 repeats located within the 59 untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene. The abnormal expansion of this triplet leads to hypermethylation and consequent silencing of the FMR1 gene. Thus, the absence of the encoded Fragile X Mental Retardation Protein (FMRP) is the basis for the phenotype. FMRP is a selective RNA-binding protein that associates with polyribosomes and acts as a negative regulator of translation [3]. FMRP appears to play an important role in synaptic plasticity by regulating the synthesis of proteins encoded by certain mRNAs localized in the dendrite.

The patients with fragile X syndrome have more dendritic spines than normal, and the spines are longer and thinner. Furthermore, patients with fragile X syndrome have more spines per unit length of dendrite. Spines regulate many neurochemical events related to synaptic transmission and modulate synaptic efficacy. The development and modification of synaptic connections involves the integration of intrinsic cellular mechanisms and extrinsic information [4]. Many protein-protein interactions and protein modifications, such as phosphorylation and ubiquitylation regulate the synaptic connections. Protein synthesis and degradation in dendrites and the cell body is another important aspect of synaptic regulation. Therefore, it is important to understand the process of selection of mRNAs from the entire pool within the nucleus required at synapses, and also the transportation along neuronal processes and their translation in a regulated manner in response to presynaptic inputs.

In the brain, FMRP is located in the cytoplasm and nucleus of neurons, majorly in the cytoplasm. The study of various FMRP truncation proteins has led to the identification of both a nuclear localization signal and a nuclear export signal in FMRP, leading to the hypothesis that FMRP shuttles into and out of the nucleus [6]. Various studies have been made to suggest that the absence of FMRP could lead to polyribosome loading of normally FMRP-associated messages, competing off ribosomes those messages with less translational attractiveness. Recent data support the interaction of FMRP with the RISC complex in regulating synaptic protein synthesis. FMRP interacts with the calcium-calmodulin-dependent kinase II (CaMKII) mRNA, from which dendritic local protein synthesis is required for memory formation [8]. The embryogenesis stage of the mouse and zebrafish is widely studied for observing the FMRP expression and is found that it diminishes in some tissues, leading to a more specific expression pattern. In humans, embryonic studies have shown FMRP expression in the central nervous system of a 9-week-old fetus whereas in a 25-week-old fetus FMRP expression was restricted to neurons [9]. In further studies on FMRP, it is discovered that FMRP can influence signaling cascades involved in morphogenesis such as Rac1, MAP1B, CaMKII, and cadherins. Thus, FXS is considered a synaptic disease. Protein synthesis in cell bodies and dendritic spines is important for synaptic plasticity, as its activation can trigger certain MRNAs. Synaptic plasticity is essential for memory and learning processes and involves long-term potentiation (LTP) and long-term depression (LTD), which are associated with synapse creation and elimination in addition to synaptic transmission [3].

Depending on the brain region, synaptic plasticity is expressed pre- and/or postsynaptically. It is clear that there is no global and fundamental defect in synapses of fragile X patients, because for the most part nervous system function in patients is normal. The studies on FXS mice show change in one type of synaptic plasticity (LTD) and not in another (LTP), which indicates that the loss of FMRP may not even affect an individual synapse under all conditions. Thus, studying the translational and positional effect of FMRP on the synaptic function will provide insight into the pathogenesis of fragile X.

Synaptic activity in the brain can trigger long lasting changes in synaptic strength called long term potentiation (LTP) and long term depression (LTD). These mechanisms work in concert to contribute to learning and memory storage throughout postnatal life. One type of LTD is triggered by activation of postsynaptic group 1 metabotrope glutamate receptors (Gp1 mGluRs, comprised of mGluR1 and mGluR5), requires rapid translation of pre-existing mRNA in the post synaptic dendrites, and stimulates the loss of surface expressed synaptic AMPA and NMDA receptors. According to the study made by Huber et al, mGluR activation normally stimulates synthesis of proteins involved in stabilisation of LTD and, in addition, FMRP. The FMRP functions to inhibit further synthesis and puts a brake on LTD. They hypothesise that exaggerated LTD and/or mGluR function are responsible for several aspects of the fragile X phenotype. Their studies in the fragile X KO mouse revealed that exaggerated LTD could slow net synaptic maturation by tipping the balance away from synapse gain to synapse loss in the critical period of synaptogenesis, and therefore contribute to the developmental delay and cognitive impairment associated with the disease. The mGluR theory predicts that Gp1 mGluR antagonists have great promise as a potential treatment of the neurologic and psychiatric symptoms of fragile X expressed in adults.

The studies done by Brown et al helped in identification of the in vivo ligands of FMRP for novel therapeutic approaches towards targeted downstream of FMRP. Studies are carried out for FMRP assayable markers, using which one can screen combinatorial libraries for small molecules that rescue this phenotype and thus identify potential therapeutic agents for the treatment of fragile X syndrome. Though various issues are still unresolved and further research is required in the field of molecular mechanisms of FMRP using in vivo techniques for better understanding. Studies need to be done to understand the actual mechanism of repeat expansion and subsequent epigenetic changes in FMR1. A better understanding is needed of the role of FMRP in local protein synthesis in the dendrite, its normal role in synaptic plasticity, and the neuronal consequence of its absence.