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Phosphorylated fragile X mental retardation protein at serine 499, is reduced in cerebellar vermis and superior frontal cortex of subjects with autism: implications for fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling
Molecular Autism volume 4, Article number: 41 (2013)
Lohith et al. (Mol Autism 4:15, 2013) recently identified increased metabotropic glutamate receptor 5 (mGluR5) expression in the frontal cortex (FC) of subjects with fragile X syndrome. These results are consistent with postmortem findings in cerebellar vermis and FC of subjects with autism (Fatemi and Folsom, Mol Autism 2:6, 2011; Fatemi et al. Anat Rec 294:1635–1645, 2011), suggesting that increased mGluR5 signaling is common to multiple autism spectrum disorders. Increased mGluR5 signaling may be associated with reduced phosphorylation of fragile X mental retardation protein (FMRP), which could result in the inactivation of this protein. In the current study, we report on reduced expression of phosphorylated FMRP in cerebellar vermis of adults and children with autism and in FC of adults with autism.
We have read with great interest the recent article by Lohith et al.  regarding increased expression of metabotropic glutamate receptor 5 (mGluR5) in the frontal cortex of individuals with fragile X syndrome (FXS). The results are consistent with our published work of increased expression of mGluR5 in the superior frontal cortex of children with autism . Moreover, we have also demonstrated increased mGluR5 expression in the cerebellar vermis of children with autism . Taken together, our data and those of Lohith et al.  suggest that increased brain expression of mGluR5 may be a specific marker of autism spectrum disorders. In contrast, we have identified reduced expression of mGluR5 in the brains of subjects with schizophrenia and bipolar disorder .
Increased mGluR5 expression in autism and FXS is associated with reduced or absent expression of fragile X mental retardation protein (FMRP) . We have shown reduced FMRP expression in the cerebellar vermis and superior frontal cortex of individuals with autism [2, 3] and from the lateral cerebellum and superior frontal cortex of subjects with schizophrenia, bipolar disorder, and major depression [4, 6]. Additionally, levels of several targets of FMRP including ras-related C3 botulinum toxin substrate 1 (RAC1), homer 1, striatal-enriched protein tyrosine phosphatase (STEP), and amyloid beta A4 precursor protein (APP) are also altered significantly in subjects with autism  pointing to involvement of mGluR5-FMRP signaling abnormalities in autism. FMRP has been found to colocalize with stalled, translationally inactive polyribosomes when phosphorylated at serine 499, whereas dephosphorylated FMRP associates with actively translating ribosomes . Thus, phosphorylated FMRP is seen as a translational repressor, while dephosphorylation of FMRP, mediated by mGluR signaling, may lead to derepression of protein translation.
We have recently completed a preliminary study of serine 499 phosphorylated FMRP protein levels in the cerebellar vermis in adults (n = 5 controls and 5 adults with autism) and children (n = 3 controls and 4 children with autism), and in the superior frontal cortex in adults (n = 6 controls and 10 adults with autism) and children (n = 6 controls and 8 children with autism). All values were normalized against neuronal specific enolase (NSE) and data were expressed as ratios of phosphorylated FMRP/NSE. We found significant reductions in phosphorylated FMRP/NSE in the vermis of adults and children with autism when compared with controls (Figure 1). There was also a significant reduction in phosphorylated FMRP in the Brodman area 9 (BA9) in adults with autism, whereas there was no significant change in the BA9 of children (Figure 1). Age, gender, and postmortem interval (PMI) were examined as possible confounders. In those cases where the relationship between confounding variables and phosphorylated FMRP showed moderate or greater effect sizes (for example, r >0.3) we used analysis of covariance (ANCOVA) to co-vary their effects. In none of these cases were significant differences between controls and subjects with autism in phosphorylated FMRP changed by the presence of these covariates. Our new finding of a reduction in phosphorylated FMRP in the cerebellar vermis of children with autism may be associated with increased activity of mGluR5, which could result in dephosphorylation of FMRP, and its subsequent ubiquitination and degradation . Current basic science reports showing abnormalities in FMRP-mGluR5 signaling and their targets [1–3, 7] support the usefulness of new novel treatments in autism spectrum disorders.
Analysis of covariance
Amyloid beta A4 precursor protein
Brodman area 9
Fragile X mental retardation protein
fragile X syndrome
Metabotropic glutamate receptor 5
Neuronal specific enolase
Ras-related C3 botulinum toxin substrate 1
Striatal-enriched protein tyrosine phosphatase.
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Fatemi SH, Folsom TD: Dysregulation of fragile X mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of subjects with autism: a postmortem brain study. Mol Autism. 2011, 2: 6-10.1186/2040-2392-2-6.
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Ceman S, O’Donnell WT, Reed M, Patton S, Pohl J, Warren ST: Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet. 2003, 12: 3295-3305. 10.1093/hmg/ddg350.
Nalavadi VC, Muddashetty RS, Gross C, Bassell GJ: Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation. J Neurosci. 2012, 32: 2582-2587. 10.1523/JNEUROSCI.5057-11.2012.
Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland, Baltimore, MD (the role of the NICHD Brain and Tissue Bank is to distribute tissue, and therefore cannot endorse the studies performed or the interpretation of results); the Harvard Brain Tissue Resource Center, which is supported in part by Public Health Service grant number R24 MH068855; the Brain Endowment Bank, which is funded in part by the National Parkinson Foundation, Inc., Miami, Florida; and the Autism Tissue Program, and is gratefully acknowledged. Grant support by the National Institute of Child Health and Human Development (#5R01HD052074-01A2 and 3R01HD052074-03S1) and the Minnesota Medical Foundation Alfred and Ingrid Lenz Harrison Autism Initiative Fund to SHF is gratefully acknowledged. SHF is also supported by the Bernstein Endowed Chair in Adult Psychiatry. Grant support from an Undergraduate Research Opportunities Program (UROP) from the University of Minnesota to OGR is gratefully acknowledged. The funding body had no role in the study design, collection, analysis and interpretation of data, in the writing of the manuscript or in the decision to submit the manuscript for publication. We appreciate the statistical help provided by Dr P Thuras.
The authors declare that they have no competing interests. SH Fatemi has several patents on the use of Reelin as a diagnostic marker for neuropsychiatric disorders but has not derived any financial gains from these patents.
SHF conceived of the study, participated in its design, supervised conduct of all experiments, and contributed to the drafting of the manuscript. OGR, MKY performed western blotting experiments. TDF performed western blotting experiments and contributed to the drafting of the manuscript. All authors read and approved the final manuscript.
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Rustan, Ø.G., Folsom, T.D., Yousefi, M.K. et al. Phosphorylated fragile X mental retardation protein at serine 499, is reduced in cerebellar vermis and superior frontal cortex of subjects with autism: implications for fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling. Molecular Autism 4, 41 (2013). https://doi.org/10.1186/2040-2392-4-41
- Cerebellar vermis
- Superior frontal cortex
- Phosphorylation of FMRP