mRNPs, polysomes or granules: FMRP in neuronal protein synthesis

https://doi.org/10.1016/j.conb.2006.05.010Get rights and content

mRNA localization and regulated translation play central roles in neurite outgrowth and synaptic plasticity. A key molecule in these processes is the Fragile X mental retardation protein, FMRP, which is involved in the metabolism of neuronal mRNAs. Absence or mutation of FMRP leads to spine dysmorphogenesis and impairs synaptic plasticity. Studies that have mainly been performed on the mouse and Drosophila models for Fragile X Syndrome showed that FMRP is involved in translational regulation at synapses, but even 15 years after discovery of the FMR1 gene, the precise working mechanisms remain elusive.

Introduction

Mental retardation is a frequent cause of cognitive disability that includes a substantial genetic component. Mutations of the gene coding for FMRP (Fragile Mental Retardation Protein) are associated with an X-linked and syndromic form of mental retardation, the Fragile X Syndrome (FXS) [1•, 2, 3, 4, 5]. In the majority of cases, the syndrome is caused by expansion of a polymorphic CGG repeat located in the 5′ UTR of the gene. The expansion causes transcriptional silencing of the FMR1 gene, which occurs as a result of hypermethylation of the CGG repeats and the upstream CpG (region with at least 200 bp and with a GC percentage that is greater than 50%) islands [6].

The domain structure of FMRP includes three RNA-binding motifs that are typical of hnRNP (heterogeneous nuclear ribonucleoprotein) proteins, namely two ribonucleoprotein K homology domains (KH domains), and a cluster of arginine and glycine residues (RGG box). A fourth domain at the N-terminus that contains a helix-loop-helix–Tudor motif also binds RNA. This domain structure suggests that FMRP is involved in messenger RNA (mRNA) biogenesis and metabolism [1]. The absence of or mutations in FMRP lead to the defects in spine morphology that are found in FXS. Indeed, FMRP has been detected along dendrites [7] and at synapses [8] where it regulates synaptic protein synthesis [9]. mRNAs are localized and translated locally at the neurites, which spatially restricts gene expression within neurons, and thereby provides growth cones and synapses with the capacity to autonomously regulate their structure and function and to alter their individual protein composition. FMRP appears to be a key regulator of this process.

In this review, we summarize recent progress on the association of FMRP with different components and regulators of the translational machinery. Taking into account recent progress in translational control, we present a new perspective on the published literature.

Section snippets

Roles of FMRP in translation and molecular mechanisms

It has been hypothesized that FMRP has a role in the regulation of neuronal translation. mRNA translation (a process divided into several pre-initiation steps of initiation, elongation and termination) can be inhibited mainly at the initiation steps but also during elongation [10, 11]. Because translation initiation complexes are smaller than a ribosome (80S; S: Svedberg unit), sedimentation on sucrose gradients, which measures complex size after ultracentrifugation, is traditionally taken as

Roles of FMRP in synaptic plasticity

The key deficit of FXS patients, similar to the situation in the mouse and fly models of the syndrome, is an immature — long and thin — appearance of the dendritic spines, which is thought to be the cause of the mental retardation [1•, 53, 54]. Spines are dynamic structures that mature during development and in response to stimulation, and this process requires local protein synthesis [55]. FMRP regulates synaptic protein synthesis [9]. To understand the mental retardation, it is, therefore,

Conclusions

Mental retardation and dendritic spine dysmorphogenesis could reflect a lack of proper dendritically localized protein synthesis. Because FMRP is expressed not only during development but also in adulthood, it is tempting to hypothesize that in addition to a role in establishing new connections, FMRP also has a role in maintaining them throughout the lifetime of an organism. The future challenge that remains in order to find a therapeutical approach to Fragile X Syndrome is the identification

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

F Zalfa is supported by a fellowship of the Italian Fragile X Syndrome Association, T Achsel by a grant from Ministero della Salute and C Bagni by grants from Istituto Superiore di Sanità, Ministero dell’Istruzione, dell’Università e della Ricerca (FIRB) and Ministero della Salute.

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