Reduced excitatory amino acid transporter 1 and metabotropic glutamate receptor 5 expression in the cerebellum of fragile X mental retardation gene 1 premutation carriers with fragile X-associated tremor/ataxia syndrome

Abstract

A premutation (PM) expansion (55–200 CGG) in the fragile X mental retardation gene 1 (FMR1) causes elevated mRNA and reduced FMR1 protein (FMRP). Young PM carriers can develop characteristic physical features and mild cognitive disabilities. In addition, individuals with PM, particularly male carriers, are at high risk to develop Fragile X-associated tremor/ataxia syndrome (FXTAS) with aging. Human post-mortem FXTAS brains show extensive white matter disease in the cerebellum and the presence of intranuclear inclusions throughout the brain, although their etiological significance is unknown. In the current work, expression levels of the metabotropic glutamate (Glu) receptor mGluR5 and the Glu transporter EAAT1, examined by RT-PCR and WB analyses, were found to be reduced in the post-mortem cerebellum of PM carriers with FXTAS compared to age matched controls, with higher CGG repeat number having greater reductions in both proteins. These data suggests a dysregulation of Glu signaling in PM carriers, which would likely contribute to the development and severity of FXTAS.

GABA receptor subunit distribution and FMRP–mGluR5 signaling abnormalities in the cerebellum of subjects with schizophrenia, mood disorders, and autism

“…The discrepancy between our results and those of other laboratories (Corti et al, 2011; Gupta et al, 2005; Matosin et al, 2013, 2014; Ohnuma et al, 2000; Pretto et al, 2014; Richardson-Burns et al, 2000; Volk et al, 2010) may reflect region-specific differences in mGluR5 expression (BA9 vs. BA10 vs. DLPFC vs. ACC vs. cerebellum); the different analytic techniques that were used (western blotting vs. receptor binding assays vs. qRT-PCR vs. immunocytochemistry); more importantly, the lack of measurement of monomer and dimer forms of mGluR5 in three studies (Corti et al, 2011; Gupta et al, 2005; Matosin et al, 2013) and the non-quantitative technique of measuring mGluR5 by immunocytochemistry in one study (Pretto et al, 2014); and lastly, differences between levels of mRNA and protein for mGluR5. The hypothesis that brain regional expression of mGluR5 may also account for differences between studies has recently been advocated by other laboratories (Matosin et al, 2014).…”

“…Even in adults with autism, where mGluR5 levels were not significantly different than controls, ratios of mGluR5 to neuronal specific enolase (NSE) for both dimeric and total mGluR5 were increased by 96% in BA9 (Fatemi and Folsom, 2011; Fatemi et al, 2011a). In contrast, a recent article by Pretto et al (2014) demonstrated reduced expression of both FMRP and mGluR5 in cerebella of subjects with the FMR1 premutation who had been diagnosed with fragile X tremor/ataxia syndrome (FXTAS). The discrepancy between these findings and ours may be due to brain regional differences as we found non-significant reductions in mGluR5 in cerebellar vermis of adults with autism (Fatemi et al, 2011a).…”

“…Furthermore, Matosin et al (2014) measured mGluR5 using receptor autoradiography which would not be able to identify either forms of mGluR5. Similarly, a recent study by Pretto et al (2014) used immunocytochemistry to measure levels of mGluR5 whereby molecular species of mGluR5 could not be identified or quantified and reported a reduction in mGluR5 in FXS-ataxia syndrome. Similarly, three groups measured mRNA levels of mGluR5 in schizophrenia and did not report any changes in hippocampus, thalamus, BA9, or BA42 (Ohnuma et al, 2000; Richardson-Burns et al, 2000; Volk et al, 2010).…”

Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

“…Patients have been described previously (Cases LR, 58-02-WD and 1007-05-HP from Greco et al., 2006 and Pretto et al., 2014). Fibroblasts of three FXTAS male individuals with confirmed pre-mutation of 84, 90, and 99 CGG repeats were obtained with the informed consent of individuals and approved by the Institutional Review Board of the Hospital La Pitié Salpêtrière.…”

Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice

“…However, as in unmethylated FXS patients, the repeat RNA forms a hairpin loop that impairs FMRP translation [5, 6]. This effect is repeat length dependent, such that larger CGG repeats elicit greater impairments in translational efficiency and lower FMRP levels [3, 7, 8]. Consistent with reduced FMRP levels, younger premutation carriers can develop symptoms more commonly associated with FXS, such as higher rates of autistic and attention deficit hyperactivity disorder (ADHD)-like symptoms [5, 9].…”