Local Protein Synthesis and Spine Morphogenesis: Fragile X Syndrome and Beyond

Department of Psychology, University of Illinois, Urbana-Champaign, Urbana, Illinois, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2006; 26(27):7151-5. DOI: 10.1523/JNEUROSCI.1790-06.2006
Source: PubMed


Behavioral experiences can modulate neural networks through changes in synaptic morphology and number. In contrast, abnormal morphogenesis of dendritic spines is associated with cognitive impairment, as in Fragile X syndrome. Dendritic or synaptic protein synthesis could provide the specificity and speed necessary for spine morphogenesis. Here, we highlight locally translated proteins shown to affect synaptic morphology (e.g., Fragile X mental retardation protein).

3 Reads
  • Source
    • "The current concept is that absence of FMRP induces translation dysregulation and defects in mRNA transport that are thought to alter local protein synthesis essential for synaptic development and maturation [3], [10]–[12]. One of the consequences of the lack of FMRP is the presence of abnormal looking immature and supernumerary neuronal dendritic spines in the brains of fragile X patients [13], [14], that ultimately lead to mental retardation in FXS patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fragile X syndrome is caused by the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein. FMRP is associated with messenger RiboNucleoParticles (mRNPs) present in polyribosomes and its absence in neurons leads to alteration in synaptic plasticity as a result of translation regulation defects. The molecular mechanisms by which FMRP plays a role in translation regulation remain elusive. Using immunoprecipitation approaches with monoclonal Ab7G1-1 and a new generation of chicken antibodies, we identified Caprin1 as a novel FMRP-cellular partner. In vivo and in vitro evidence show that Caprin1 interacts with FMRP at the level of the translation machinery as well as in trafficking neuronal granules. As an RNA-binding protein, Caprin1 has in common with FMRP at least two RNA targets that have been identified as CaMKIIα and Map1b mRNAs. In view of the new concept that FMRP species bind to RNA regardless of known structural motifs, we propose that protein interactors might modulate FMRP functions.
    PLoS ONE 09/2012; 7(6):e39338. DOI:10.1371/journal.pone.0039338 · 3.23 Impact Factor
  • Source
    • "It has been suggested that neurological and psychiatric symptoms associated with FraX may be a consequence of an exaggerated response to metabotrophic glutamate receptor (mGluR) activation due to an absence/reduction of FMRP [36]. FMRP modulates dendritic maturation and synaptic plasticity and one of the mechanisms postulated for this effect is its inhibition of the metabotrophic Glu receptors (mGluR), mGluR1 and mGluR5 mediated mRNA translation in dendrites [37,38]. In mouse models the mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP) has been shown to reverse behavioral phenotypes (including hyperactivity, seizures, pre-pulse inhibition deficits, repetitive behaviors) and to lead to remarkable improvements in synaptic plasticity and spine morphology [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing evidence that neurodevelopmental differences in people with Fragile X syndrome (FraX) may be explained by differences in glutamatergic metabolism. Premutation carriers of FraX were originally considered to be unaffected although several recent reports demonstrate neuroanatomical, cognitive, and emotional differences from controls. However there are few studies on brain metabolism in premutation carriers of FraX. We used proton magnetic resonance spectroscopy to compare neuronal integrity of a number of brain metabolites including N-Acetyl Aspartate, Creatine + Phosphocreatinine, Choline, myoInositol, and Glutamate containing substances (Glx) in 17 male premutation carriers of FraX and 16 male healthy control individuals. There was no significant between-group difference in the concentration of any measured brain metabolites. However there was a differential increase in N-acetyl aspartate with aging in premutation FraX individuals compared to controls. This is the first 1 H-MRS study to examine premutation FraX individuals. Although we demonstrated no difference in the concentration of any of the metabolites examined between the groups, this may be due to the large age ranges included in the two samples. The differential increase in NAA levels with aging may reflect an abnormal synaptic pruning process.
    Journal of Neurodevelopmental Disorders 08/2012; 4(1):23. DOI:10.1186/1866-1955-4-23 · 3.27 Impact Factor
  • Source
    • "Fragile-X syndrome (FXS) (OMIM 300624) is caused by the expansion of the CGG repeat in the 5′ untranslated region (UTR) of fragile X mental retardation 1 (FMR1) gene (OMIM 309550) located on the X chromosome (Fu et al., 1991, Verkerk et al., 1991). The prevalence of FXS is estimated at ~1/4000 males and ~1/8000 females which have been substantiated by other reports (Crawford et al., 2001, Coffee et al., 2009, Garber et al., 2006, Turner et al., 1996, Murray et al., 1996,). In over 98% of the patients, FXS is caused by expansion of the triplet repeats in addition, others have reported rare single point mutations and genetic variants also cause FXS without expansion of the CGG repeat (Collins et al., 2010, De Boulle et al., 1993, Tarleton et al., 2002,). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fragile X syndrome (FXS) is characterized by moderate to severe intellectual disability, which is accompanied by macroorchidism and distinct facial morphology. FXS is caused by the expansion of the CGG trinucleotide repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. The syndrome has been studied in ethnically diverse populations around the world and has been extensively characterized in several populations. Similar to other trinucleotide expansion disorders, the gene-specific instability of FMR1 is not accompanied by genomic instability. Currently we do not have a comprehensive understanding of the molecular underpinnings of gene-specific instability associated with tandem repeats. Molecular evidence from in vitro experiments and animal models supports several pathways for gene-specific trinucleotide repeat expansion. However, whether the mechanisms reported from other systems contribute to trinucleotide repeat expansion in humans is not clear. To understand how repeat instability in humans could occur, the CGG repeat expansion is explored through molecular analysis and population studies which characterized CGG repeat alleles of FMR1. Finally, the review discusses the relevance of these studies in understanding the mechanism of trinucleotide repeat expansion in FXS.
    Annals of Human Genetics 12/2011; 76(2):178-91. DOI:10.1111/j.1469-1809.2011.00694.x · 2.21 Impact Factor
Show more

Similar Publications

Preview (2 Sources)

3 Reads
Available from