mRNPs, polysomes or granules: FMRP in neuronal protein synthesis
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.
References (68)
- et al.
Preface: fragile X syndrome: frontiers of understanding gene-brain-behavior relationships
Ment Retard Dev Disabil Res Rev
(2004) - et al.
Understanding the biological underpinnings of fragile X syndrome
Curr Opin Pediatr
(2003) - et al.
Molecular mechanisms of translational control
Nat Rev Mol Cell Biol
(2004) - et al.
Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome
Cell
(2001) - et al.
The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2
EMBO J
(1995) - et al.
Kinesin transports RNA: isolation and characterization of an RNA-transporting granule
Neuron
(2004) - et al.
The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain
Proc Natl Acad Sci USA
(2005) - et al.
Post-transcriptional gene silencing by siRNAs and miRNAs
Curr Opin Struct Biol
(2005) - et al.
Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway
Nat Neurosci
(2004) - et al.
Synaptic protein synthesis associated with memory is regulated by the RISC pathway in drosophila
Cell
(2006)
Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies
Nat Cell Biol
Trapping of messenger RNA by fragile X mental retardation protein into cytoplasmic granules induces translation repression
Hum Mol Genet
Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes
Genes Dev
A role for the cytoplasmic polyadenylation element in NMDA receptor-regulated mRNA translation in neurons
J Neurosci
Dynamic visualization of local protein synthesis in hippocampal neurons
Neuron
Coupling the iron-responsive element to GFP -an inducible system to study translation in a single living cell
Sci STKE
From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome
Nat Rev Neurosci
Fathoming fragile X in fruit flies
Trends Genet
The mGluR theory of fragile X mental retardation
Trends Neurosci
Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome
Science
Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses
J Neurosci
Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes
J Neurosci
The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses
Cell
Biochemical mechanisms for translational regulation in synaptic plasticity
Nat Rev Neurosci
Stress granules: sites of mRNA triage that regulate mRNA stability and translatability
Biochem Soc Trans
Molecular biology. P-bodies mark the spot for controlling protein production
Science
A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies
RNA
A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay
J Cell Biol
Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles
Proc Natl Acad Sci USA
Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells
J Neurosci
Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them
Mol Cell Biol
Casein kinase II phosphorylates the fragile X mental retardation protein and modulates its biological properties
Mol Cell Biol
A drosophila fragile X protein interacts with components of RNAi and ribosomal proteins
Genes Dev
FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association
Mol Cell
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