Fragile X mental retardation, the most common form of inherited mental impairment, is caused by mutations in the fmr-1 gene, coding for fragile X mental retardation protein (FMRP). A body of circumstantial evidence has suggested that neuronal FMRP plays a role in protein translation, particularly local dendritic translation in response to synaptic activity. These findings open the possibility that FMRP could play a critical role in the synaptic plasticity believed to underlie learning and memory, functions that are severely affected in Alzheimer disease.

In an article published 17 November 2004 in the early online edition of PNAS, William Greenough's team at the University of Illinois at Urbana-Champaign, demonstrate the importance of FMRP by showing what happens when the protein is absent. Greenough and colleagues found that mice with the fmr-1 gene knocked out have deficits in dendritic protein translation, specifically in their ability to upregulate protein synthesis in response to neurotransmitter activation of postsynaptic receptors.

This year has seen the publication of several studies that add detail to the role of FMRP in postsynaptic membranes. Two research groups confirmed that FMRP participates in complexes with polyribosomes (Khandjian et al., 2004; Stefani et al., 2004), and other researchers demonstrated that FMRP is rapidly transported into dendrites in response to KCl depolarization (Antar et al., 2004). In their study, Greenough, first authors Ivan Jeanne Weiler and Chad Spangler, and colleagues studied the dendritic protein translation machinery in tissue from two-week-old fmr-1 KO mice, which have a phenotype reminiscent of human fragile X syndrome, including immature dendritic spine morphology.

Weiler and colleagues worked with preparations called "synaptoneurosomes." These are derived from tissue that is homogenized and passed through successively smaller filters, leaving behind subcellular particles containing neuronal processes, including intact synapses. Pools of synaptoneurosomes can be stimulated with receptor agonists or KCl to simulate synaptic transmission.

In agreement with earlier studies, Weiler and colleagues found that wild-type synaptoneurosomes from visual cortex responded to K+ depolarization with rapid (within two minutes) assembly and incorporation of mRNA into polyribosomes (P-mRNA). By contrast, synaptoneurosomes from the knockout mice lacked this ability. Similarly, agonist stimulation of metabotropic glutamate receptors (mGluRs) induced rapid increases in P-mRNA in the wild-type, but not the fmr-1 KO mice.

Supporting the notion that FMRP is critical to local dendritic, activity-dependent protein translation, the authors found that FMRP-negative preparations were deficient in protein synthesis. Five minutes after mGluR stimulation, synaptoneurosomes from wild-type mice showed a burst of translational activity, as indicated by incorporation of radioactively labeled methionine. In contrast, synaptoneurosomes from the KO mice were unable to respond with increased protein synthesis in this time frame.

To address the concern that mGlu receptors might be downregulated in the KO mice, the authors bypassed the receptors and directly stimulated protein kinase C, which lies downstream of mGluR in the pathway that promotes rapid assembly of polyribosomes. This also failed to activate the dendritic translation machinery in the fmr-1 KO mice. Finally, Weiler and colleagues used electron microscopy to examine layer IV visual cortical tissue, finding that a significantly lower proportion of synapses in the fmr-1 KO mice had polyribosome assemblies in their vicinities.

Speculation has given FMRP several possible roles in regulation of protein translation, including the transport of mRNA and a role in the actual translation process. The authors suggest a model whereby FMRP binds certain mRNAs as early as in the nucleus, before the mRNA complex is transported to the dendrites. There, FMRP remains bound to the mRNA until signaled in some way by synaptic activity. Then the mRNA, according to this model, is released for rapid translation at polyribosomes near synapses.

What proteins might be impacted by the absence of FMRP? One group is neurotransmitters, speculate the authors. Any diminution in proteins critical for receptor proliferation in the postsynaptic membrane might have effects on synaptic plasticity, and hence, one might extrapolate, on processes critical for learning and memory.—Hakon Heimer

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  1. Various forms of mental retardation and neurodegenerative disorders are associated with defects in the density and morphology of dendritic spines (Fiala et al., 2002). Fragile X syndrome (FXS), the most common inherited cause of mental retardation, is characterized by a hyperabundance of dendritic spines having a long, thin, and apparently immature morphology. FXS is caused by a trinucleotide repeat expansion that silences the FMR1 gene and leads to a loss of the encoded Fragile X mental retardation protein (FMRP). FMRP is an mRNA binding protein that is hypothesized to play important roles in the activity-dependent transport and/or translation of mRNAs at postsynaptic sites of dendritic spines. One attractive hypothesis is that the loss of FMRP may impair activity-dependent translation that is essential for spine maturation and long-term synaptic plasticity.

    In this study by Ivan-Jeanne Weiler, William Greenough, and colleagues (PNAS 2004), the authors have shown for the first time that there is impaired stimulus-induced translation in synaptosomes isolated from visual cortex of FMR1 knockout mice. Using two approaches, polyribosomal incorporation and methionine incorporation, they found that activation of group I metabotropic glutamate receptors robustly stimulated protein synthesis in synaptosomes from wild-type, but not from knockout mice. Such translational impairments were corroborated in vivo using electron microscopy, which showed a reduced frequency of spine synapses containing polyribosomal aggregates. These findings indicate that FMRP is necessary for the glutamatergic stimulation of synaptic protein synthesis.

    Future studies will need to be done to identify specific mRNA targets for FMRP, translational impairment of which may underlie the spine defects observed in FXS. For example, there may be defects in the local synthesis of proteins that are involved in the scaffolding or regulation of glutamate receptors within the postsynaptic density. Alternatively, the hyperabundance of immature spines in FXS may reflect a compensatory process that is due to impaired synaptic input and/or protein synthesis-dependent plasticity. The age-old question of cause versus consequence; pre- versus postsynaptic changes emerge here as well in FXS, as is the case for neurodegenerative disorders such as Alzheimer disease. While this new study does not solve this riddle, it does move the field forward greatly, as we now have an important link between FMRP, the synapse, and protein synthesis-dependent plasticity.

    References:

    . Dendritic spine pathology: cause or consequence of neurological disorders?. Brain Res Brain Res Rev. 2002 Jun;39(1):29-54. PubMed.

  2. This is a timely report, since it has been recently shown that FMRP is definitely associated with brain polyribosomes (see Stefani et al., 2004 and Khandjian et al., 2004). The data reported by Weiler et al. show that synaptoneurosomes from the Fragile X mental retardation 1 knockout mice do not exhibit neurotransmitter-induced rapid formation of polyribosomes and accelerated protein synthesis as compared to synaptoneurosomes derived from wild-type animals. The deficit in translation in the KO preparations is apparently due to the absence of FMRP. These results obtained in vitro corroborate with the observation that in the absence of FMRP in KO mice, a significantly lower proportion of synapses containing Postsynaptic Polyribosomal Aggregates (PRAs) is observed. As proposed by the authors, one possible explanation for the reduced synaptic translation in KO mice is that FMRP might play a role in targeting mRNAs for transport to synaptic sites. However, it is not known whether the reduced number of polyribosomes in synapses is due to the reduced transport of mRNPs (feedback reaction?) or possibly to lower synthesis of ribosomes, as FMRP also controls translation of different species of mRNA in the soma. The findings described here are extremely important and will have impacts in our thinking about the role of FMRP in cellular processes and in the missing function(s) in the Fragile X Syndrome. It is possible that these findings will open new avenues and new comprehension for other neuronal diseases, perhaps in the translational control.

    References:

    . Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci. 2004 Aug 18;24(33):7272-6. PubMed.

    . Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13357-62. PubMed.

References

Paper Citations

  1. . Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13357-62. PubMed.
  2. . Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci. 2004 Aug 18;24(33):7272-6. PubMed.
  3. . Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses. J Neurosci. 2004 Mar 17;24(11):2648-55. PubMed.

Further Reading

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Primary Papers

  1. . Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17504-9. PubMed.