We conclude that loss of FMRP results in significant epigenetic misregulation and that targeting transcription via epigenetic regulators like Brd4 may provide new treatments for FXS.
We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should be performed in patients with typical symptoms of fragile X syndrome in whom no CGG repeat expansion is detected.
We conclude that further studies including western blot and DNA sequence analysis of the FMR1 gene should be performed in patients with typical symptoms of fragile X syndrome in whom no CGG repeat expansion is detected.
We compared the performance of individuals affected by FXS to typically developing individuals of equivalent mental age as well as the performance of Fmr1 knockout mice to wild-type control mice on the same maze problems.
We checked brain energy status and some aspects of cell bioenergetics, namely the activity of key glycolytic enzymes, glycerol-3-phosphate shuttle and mitochondrial respiratory chain (MRC) complexes, in the cerebral cortex of the Fmr1 knockout (KO) mouse model of FXS.
We believe we report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes.
We assessed genome-wide and FMR1-specific DNA methylation in 32 males previously diagnosed with FXS, including nine with mosaicism, as well as five females with full mutation, and premutation carrier males (n = 11) and females (n = 11), who were compared to 300 normal control DNA samples.
We also observed genotypic differences characteristic of the FXS phenotype in Fmr1 KO mice, such as enhanced prepulse inhibition and repetitive behavior, hyperactivity, and reduced startle responses (p < 0.05).
Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression.
Using metabolomics, in vivo metabolic phenotyping of the Fmr1-KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization.
Unlike fragile X syndrome (FXS), FMR1 expression in response to α-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB).
Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome.
Twenty children and adolescents (aged 6-17 years) with a diagnosis of FXS (confirmed through molecular documentation of FMR1 full mutation) were enrolled in an open-label, multi-site, trial of ZYN002.
Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS.
Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.
To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1<sup>-/-</sup>) mouse model of Fragile X syndrome.
To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements.
To study the involvement of the FMR-1 gene in the fragile X syndrome, its expression was studied in lymphoblastoid cell lines and leukocytes derived from patients and normal controls.
To functionally connect Fmr1-deficiency to its metabolic biomarkers, we derived a functional interaction network based on the existing knowledge (literature and databases) and show that the FXS metabolic response is initiated by distinct mRNA targets and proteins interacting with FMRP, and then relayed by numerous regulatory proteins.
To elucidate cellular mechanisms involved in the pathogenesis of FXS, we compared dendritic spines in the hippocampal CA1 region of adult wild-type (WT) and Fmr1 knockout (Fmr1-KO) mice.
To determine whether AFQ056 may have secondary effects on the methylation and transcription of FMR1, here we treated three FXS lymphoblastoid cell lines and one normal control male line.