Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum toxin substrate 1, amyloid beta A4 precursor protein, striatal-enriched protein tyrosine phosphatase, and homer 1, in autism: a postmortem study in cerebellar vermis and superior frontal cortex

Fatemi, S. Hossein; Folsom, Timothy D.; Kneeland, Rachel E.; Yousefi, Mahtab K; Liesch, Stephanie B.; Thuras, Paul

doi:10.1186/2040-2392-4-21

Cited by 63 publications

(53 citation statements)

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“…Within this data set, 111 proteins from 183 complexes corresponded to proteins changed at P17. Notably, four of the six components in the postsynaptic GluRδ-2 receptor complex, including autism-susceptible genes Shank1, Shank2, and homer (30)(31)(32), and four of the five components in the NDMA receptor complex were significantly up-regulated. All four components in the presynaptic vesicle SNARE complex were also significantly up-regulated.…”

Section: Differentially Expressed Proteins In Fmr1 Ko Mice Show Gene mentioning

confidence: 99%

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

Tang

Wang

Wan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by severe intellectual disability and other symptoms including autism. Although caused by the silencing of a single gene, Fmr1 (fragile X mental retardation 1), the complexity of FXS pathogenesis is amplified because the encoded protein, FMRP, regulates the activity-dependent translation of numerous mRNAs. Although the mRNAs that associate with FMRP have been extensively studied, little is known regarding the proteins whose expression levels are altered, directly or indirectly, by loss of FMRP during brain development. Here we systematically measured protein expression in neocortical synaptic fractions from Fmr1 knockout (KO) and wild-type (WT) mice at both adolescent and adult stages. Although hundreds of proteins are up-regulated in the absence of FMRP in young mice, this up-regulation is largely diminished in adulthood. Up-regulated proteins included previously unidentified as well as known targets involved in synapse formation and function and brain development and others linked to intellectual disability and autism. Comparison with putative FMRP target mRNAs and autism susceptibility genes revealed substantial overlap, consistent with the idea that the autism endophenotype of FXS is due to a "multiple hit" effect of FMRP loss, particularly within the PSD95 interactome. Through studies of de novo protein synthesis in primary cortical neurons from KO and WT mice, we found that neurons lacking FMRP produce nascent proteins at higher rates, many of which are synaptic proteins and encoded by FMRP target mRNAs. Our results provide a greatly expanded view of protein changes in FXS and identify age-dependent effects of FMRP in shaping the neuronal proteome.fragile X | quantitative mass spectrometry | synaptic protein synthesis | autism | stable isotope labeling F ragile X syndrome (FXS) is an X-linked monogenic disorder that leads to highly debilitating changes in neurodevelopment. Affected individuals exhibit mental retardation, attention deficit and hyperactivity, anxiety, autism spectrum behaviors, and other symptoms that compound overall impairment (1). In the vast majority of cases, FXS is caused by an mRNA-dependent epigenetic silencing of the Fmr1 (fragile X mental retardation 1) gene (2), which occurs secondarily to a CGG repeat expansion in the 5′ UTR region of Fmr1 (3) and results in absence of the encoded protein FMRP. FMRP is an RNA-binding protein that regulates several aspects of mRNA translation (1), transport (4), and stability (5) in neurons. Substantial evidence indicates that FMRP is particularly critical as a suppressor of activity-dependent mRNA translation at glutamatergic synapses (6, 7) and that loss of this function results in abnormalities in dendritic spine shape and several forms of long-term synaptic plasticity (8, 9). In addition, significant changes have been described regarding the structure and/or function of other synaptic systems, including GABAergic and endocannabinoid synapses (10, 11). Loss of FMR...

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Section: Differentially Expressed Proteins In Fmr1 Ko Mice Show Gene mentioning

confidence: 99%

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

Tang

Wang

Wan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Consistent with the idea that FXS is a disease of exaggerated protein translation, previous work in our laboratory has shown that levels of Rac1-GTP (active form of Rac1) are elevated in males Fmr1 knockout mouse in the C57Bl6/J strain (Bongmba et al, 2011). Additionally, other laboratories have reported that humans with FXS have also significant levels of the small GTPase Rac1 (Fatemi et al, 2013). Thus, we also examined whether levels of Rac1-GTP are altered in this female FXS model developed in the FVB.129 background.…”

Section: Resultsmentioning

confidence: 55%

“…Female FVB.129-Fmr1 knockout (KO) mice were found to have deficient memory and altered auditory skills as reported previously for their male counterpart. Furthermore, as recently reported in FXS humans (Fatemi et al, 2013) and male KO mice (Bongmba et al, 2011), levels of the small GTPase Rac1 were found to be elevated in the female KO mice. In an attempt to normalize levels of Rac1 to decode whether this protein has a role in behavioral deficits, we observed that treatment with Rac1 inhibitors improved cognitive capabilities and protected against audiogenic seizures outcomes.…”

Section: Introductionmentioning

confidence: 62%

“…Interestingly, studies in a FXS animal model (Bongmba et al, 2011) as well as in FXS patients (Fatemi et al, 2013) have revealed that lack of FMRP translates in excess levels of Rac1. We hypothesize that this elevated translation of Rac1 might be responsible for the altered plasticity, aberrant phenotypic behavior and increased density of dendritic spines reported for this disease.…”

Section: Discussionmentioning

confidence: 98%

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Phenotype analysis and rescue on female FVB.129-Fmr1 knockout mice

Nguy

Tejada‐Simon

2016

Front. Biol.

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Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and a cause for autism. FXS females report milder phenotypes and a lower rate of cognitive problems compared to males. This is most likely because most females are heterozygous, while males are hemizygous for the disease. Thus, most preclinical studies have been completed in males. As there is major interest in testing experimental drugs for FXS, it is imperative to determine whether females in animal models used for research, present behavioral alterations that might translate to humans in order to confirm that experimental drugs have an effect on both genders. In our study we describe behavioral phenotypes in homozygous FXS female mice developed on the FVB.129 background. We focused on detection of hippocampal-mediated cognitive abilities and other behaviors described for FXS. Our research shows that, while female FVB.129-Fmr1 knockout mice present normal learning, they have impaired memory, as well as susceptibility to audiogenic seizures. In agreement with previous reports in rodents and humans, significant levels of the small GTPase Rac1 were found in FXS female mice. Because Rac1 is involved in neuronal development, plasticity and behavior, we additionally aimed to pharmacologically inhibit Rac1 and determine whether observed phenotypes are rescued. Treatment of female FVB.129-Fmr1 knockout with a Rac1 inhibitor abolished behavioral deficits, bringing phenotypes to control levels. Our results suggest that female FVB.129-Fmr1 knockout mice display behavioral impairments that resemble FXS in humans. Moreover, those behavioral shortfalls might be associated with alteration of plasticity involving excessive Rac1 function, since pharmacological reduction of Rac1 normalizes previously altered phenotypes to control levels.

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“…As eluded in the above, a set of unfolding evidence points toward a broader implication of FMRP role outside FXS and ASD, as abnormally low FMRP levels have also been linked to non-FXS disorders in those with a normal FMR1 genotype (i.e., major depression (MDD) and bipolar disorder (BD) [74,75] and schizophrenia [76]. Altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with autism: homer 1, APP, ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP) have been shown by Fatemi and colleagues [77]. Recently, the same group [78] investigated the expression of the same four proteins in lateral cerebella of subjects with Sch, BD, and MDD and in frontal cortex of subjects with Sch and BD.…”

Section: Neurobiological Features and Targeted Treatments In Fragile mentioning

confidence: 99%

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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SummaryFragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem worldwide, ASD is purely behaviorally defined whereas FXS is a medical/genetic disorder characterized by ID and ASD in males and learning and behavioral/emotional problems (social anxiety, attention network) in both genders. FXS is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1) that leads to the epigenetic silencing of the gene and absence of its encoded protein, the fragile X mental retardation protein (FMRP). FMRP selectively targets approximately 4% of the transcribed mRNAs in the brain. Namely, to date, 842 such target mRNAs in mammalian brains have been identified and many of them converge on the same pathway as nonsyndromic ASD. Thus, FXS is the most studied 'disorder of synapse' model for syndromic ASD in the field of neuroscience. There are currently no effective treatments for either FXS or ASD.In this review article, we discuss recent progress and future directions in translating breakthrough preclinical findings that reveal potential therapeutic targets into clinical trials for humans with FXS of potential relevance for ASD. To date, a total of 20 double-blinded, randomized, placebo-controlled clinical trials in FXS have been identified through the FDA ClinicalTrial.gov website. The majority of these trials were completed between 2008−2015. These mostly phase II trials in adults and adolescents tested 13 compounds and have primarily targeted excitatory/inhibitory imbalance theory of FXS and ASD, namely a reversal of social/behavioral symptoms that are part of the core FXS phenotype but not the core synaptic dysfunction in FXS. Despite much progress in the field propelled by the preclinical advances, these clinical studies illustrate the gaps and challenges of translating therapies from animal models to humans with FXS and ASD ('building a bridge and walking on it'). Specifically, recent challenges in the clinical trials demonstrate the need to study for longer period of time (6−12 months), prepubertal age group(s), develop more objective clinical outcome measures (i.e., clinician-based, relevant learning paradigms, and desired biomarkers), and longer placebo run-ins to minimize the placebo impact for both FXS and ASD. Ultimately, a truly satisfactory FXS, and ASD, therapy may likely involve a combination of drugs (and learning paradigms), each targeting a different aspect of the core synaptic, cognitive and behavioral impairments in FXS.

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Cited by 63 publications

References 97 publications

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

Phenotype analysis and rescue on female FVB.129-Fmr1 knockout mice

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

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