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Concept: Fragile X syndrome


Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition.

Concepts: Brain, Autism, Down syndrome, Mental retardation, Disability, Fragile X syndrome, FMR1, Dendritic spine


Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.

Concepts: Gene, Autism, Asperger syndrome, Autism spectrum, Behavior, Mouse, Mice, Fragile X syndrome


Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, a disorder which currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective PKCϵ activator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor (BDNF) expression, 2) the PSD-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without down-regulation of mGluR5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. The mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without down-regulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults.

Concepts: Psychology, Gene, Gene expression, Brain, Transcription, Hippocampus, Long-term potentiation, Fragile X syndrome


Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders is fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism. Progress in basic neuroscience has led to identification of molecular targets for treatment in FXS; however, there is a gap in translation to targeted therapies in humans. The present study introduces a novel therapeutic target for FXS: nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor known to induce expression of over 100 cytoprotective genes. We also demonstrate that NNZ2566, a drug that has successfully completed a phase 2 clinical trial in FXS, is effective in modulating this target in FXS, partially reversing the FXS phenotype: NNZ2566 has a therapeutic role as Nrf2 activator. Effectively, treatment with NNZ2566 normalizes the translocation of Nrf2 to the nucleus, inducing expression of numerous oxidative stress related genes including NQO1, GST-α1 and EH and has a knockdown effect on E-cadherin. In summary, the Nrf2/ARE pathway appears to be a novel promising therapeutic target for FXS and NNZ2566 appears to be acting as an activator of the Nrf2/ARE pathway and suggests a potential benefit across multiple symptoms that could be associated with the pathobiological processes underlying FXS.

Concepts: DNA, Gene, Genetics, Gene expression, Transcription, Autism, Mental retardation, Fragile X syndrome


Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in the pathology of this disease. The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 activation, is altered in several brain areas of Fmr1 knockout mice. We found that CB1R blockade in male Fmr1 knockout (Fmr1(-/y)) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5. Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS.

Concepts: Protein, Receptor, Autism, Metabotropic glutamate receptor, Cannabinoid receptor, Mental retardation, Fragile X syndrome, FMR1


The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression.

Concepts: Gene expression, Cancer, Breast cancer, Metastasis, Oncology, Lung cancer, Fragile X syndrome, FMR1


Fragile X syndrome, a common cause of intellectual disability and autism, is thought to occur due to abnormal regulation of neuronal protein synthesis. A study by Osterweil et al. (2013), in this issue, demonstrates that the HMG-CoA reductase inhibitor lovastatin can normalize protein synthesis and also reduce audiogenic seizures in Fmr1 knockout mice.

Concepts: Statin, Autism, Mental retardation, Fragile X syndrome, FMR1, HMG-CoA reductase, Red yeast rice, Lovastatin


Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a “premutation” size 55-200 CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Core motor features include cerebellar gait ataxia and kinetic tremor, resulting in progressive mobility disability. There are no published studies characterizing balance deficits in FMR1 premutation carriers with and without FXTAS using a battery of quantitative measures to test the sensory integration underlying postural control, automatic postural reflexes, and dynamic postural stability limits. Computerized dynamic posturography (CDP) and two performance-based balance measures were administered in 44 premutation carriers, 21 with FXTAS and 23 without FXTAS, and 42 healthy controls to compare balance and functional mobility between these groups. Relationships between FMR1 molecular variables, age, and sex and CDP scores were explored. FXTAS subjects demonstrated significantly lower scores on the sensory organization test (with greatest reductions in the vestibular control of balance), longer response latencies to balance perturbations, and reduced stability limits compared to controls. Premutation carriers without FXTAS also demonstrated significantly delayed response latencies and disrupted sensory weighting for balance control. Advancing age, male sex, increased CGG repeat size, and reduced X activation of the normal allele in premutation carrier women predicted balance dysfunction. These postural control deficits in carriers with and without FXTAS implicate dysfunctional cerebellar neural networks and may provide valuable outcome markers for tailored rehabilitative interventions. Our findings suggest that CDP may provide sensitive measures for early detection of postural control impairments in at-risk carriers and better characterize balance dysfunction and progression in FXTAS.

Concepts: Male, Allele, Ataxia, Mental retardation, Fragile X syndrome, FMR1, 1999 albums, The Fragile


Fragile X syndrome (FXS), caused by the loss of functional FMRP, is a leading cause of autism. Neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, we identify that, in Fmr1 knockout neurons, type 1 adenylyl cyclase (Adcy1) mRNA translation is enhanced, leading to excessive production of ADCY1 protein and insensitivity to neuronal stimulation. Genetic reduction of Adcy1 normalizes the aberrant ERK1/2- and PI3K-mediated signalling, attenuates excessive protein synthesis and corrects dendritic spine abnormality in Fmr1 knockout mice. Genetic reduction of Adcy1 also ameliorates autism-related symptoms including repetitive behaviour, defective social interaction and audiogenic seizures. Moreover, peripheral administration of NB001, an experimental compound that preferentially suppresses ADCY1 activity over other ADCY subtypes, attenuates the behavioural abnormalities in Fmr1 knockout mice. These results demonstrate a connection between the elevated Adcy1 translation and abnormal ERK1/2 signalling and behavioural symptoms in FXS.

Concepts: DNA, Gene expression, Transcription, Ribosome, Protein biosynthesis, Autism, Fragile X syndrome, FMR1


Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.

Concepts: DNA, Protein, Gene, Genetics, RNA, Autism, Mental retardation, Fragile X syndrome