Fragile X mental retardation protein levels are decreased in major psychiatric disorders

Abstract

In individuals with fragile X syndrome (FXS), there is a silencing of the fragile X mental retardation (FMR1) gene, usually due to an expansion of a CGG repeat in the 5' untranslated region (Oostra and Willemsen, 2009). The subsequent loss of the FMR1 gene product, fragile X mental retardation protein (FMRP), an RNA-binding protein that travels between the nucleus and cytoplasm, results in disruption of post-transcriptional regulation of many target RNAs (De Rubeis and Bagni, 2010), leading ultimately to multiple pathologies associated with FXS.FXS is characterized by mental retardation and autistic behavior. Indeed many cases of FXS also have overlapping diagnoses of autism, with one source estimating approximately 47% overlap (Demark et al., 2003). Recently, our laboratory has discovered significant reductions of FMRP in post-mortem autistic cerebella and superior frontal cortex (Fatemi et al.., 2010a,b,c). When compared to matched controls, we observed a 75% reduction in FMRP expression (p<0.038) in cerebella of adults with autism and a 50% reduction in FMRP expression (p<0.042) in superior frontal cortex of adults with autism (Fatemi et al., 2010a,c). Associations between FMR1 dysregulation and other major psychiatric disorders have not been extensively studied, however an association between cytoplasmic FMR1 (CYFIP1) and schizophrenia has been examined (Tam et al., 2010). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The goal of the present study was to examine the levels of FMRP in the lateral cerebella of patients with diagnoses of schizophrenia, bipolar disorder, and major depression as compared to controls. Our hypothesis was that FMRP expression would be decreased in these subjects as compared to normal control subjects. NIH Public AccessAll experimental procedures were approved by the Institutional Review Board of the University of Minnesota School of Medicine. Postmortem blocks of lateral cerebellum were obtained from the Stanley Medical Research Institute. Samples were stored at −80°C until use and derived from four groups (n=15 from subjects with bipolar disorder; n=13 from subjects with major depression; n=12 from subjects with schizophrenia; n=14 from control subjects). Tissues were homogenized, assayed for total protein concentration, and protein was isolated via SDS-PAGE and western blotting as previously described (Fatemi et al., 2008). The blots were incubated with anti-FMRP (Millipore) or anti-β-actin (Sigma Aldrich) and subsequently exposed to the appropriate secondary antibody. Sample densities were analyzed blind to diagnostic nature of the tiss...

The Psychiatric Presentation of Fragile X: Evolution of the Diagnosis and Treatment of the Psychiatric Comorbidities of Fragile X Syndrome

“…Further evidence that FMRP may be involved in the regulation of major neurotransmitter systems, and that its absence can directly lead to psychiatric symptoms is supplied by a preliminary report of low levels of FMRP among non-fragile X patients with major psychopathology [Fatemi et al, 2010]. Larger studies examining FMRP levels in non-fragile X populations with autism and other major psychiatric disorders are warranted, as FMRP may be a key regulator not only of learning and memory, but also of mood and anxiety.…”

Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders

“…Emerging evidence suggests that downregulation of fragile X mental retardation protein (FMRP) may be common to multiple psychiatric disorders including autism, schizophrenia, bipolar disorder, and major depression, rather than simply a hallmark of fragile X syndrome (FXS) (Fatemi et al, 2010a, 2011a, 2013a,b; Fatemi and Folsom, 2011, 2014; Fernandez et al, 2013; Kelemen et al, 2013; Kovács et al, 2013; Jacquemont et al, 2014). In FXS, reduced FMRP is the result of gene silencing of the Fragile X mental retardation 1 gene (FMR1).…”

Identification of Expanded Alleles of the FMR1 Gene in the CHildhood Autism Risks from Genes and Environment (CHARGE) Study

“…One proximal mechanism contributing to ASD risk in FXS is the loss of the FMR1 protein (FMRP) (Hagerman et al 2008). Indeed, recent reports indicate that FMRP may be deficient in other disorders including autism not associated with FXS (Fatemi and Folsom 2011), schizophrenia, bipolar disorder, and even depression (Fatemi et al 2010). Finally, many studies over the past 25 years have documented the higher incidence of ASD in subjects with FXS (Reddy 2005).…”