Weiler IJ, Spangler CC, Klintsova AY, Grossman AW, Kim SH, Bertaina-Anglade V, Khaliq H, de Vries FE, Lambers FA, Hatia F, Base CK, Greenough WT. 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.
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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:
Fiala JC, Spacek J, Harris KM. Dendritic spine pathology: cause or consequence of neurological disorders?. Brain Res Brain Res Rev. 2002 Jun;39(1):29-54. PubMed.
View all comments by Gary BassellThis 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:
Stefani G, Fraser CE, Darnell JC, Darnell RB. Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J Neurosci. 2004 Aug 18;24(33):7272-6. PubMed.
Khandjian EW, Huot ME, Tremblay S, Davidovic L, Mazroui R, Bardoni B. 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.
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