Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain

Gholizadeh, Saber; Halder, Sebok Kumar; Hampson, David R.

doi:10.1016/j.brainres.2014.11.023

Cited by 82 publications

(89 citation statements)

References 33 publications

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“…Thus, neuron-specific expression of FMRP using either Syn-FMRP or Syn-mCMV-FMRP is consistent with the native endogenous FMRP expression, which is predominantly neuronal in the adult mouse brain. 11 Therefore, the main difference between the two FMRP vectors was the amount of FMRP expressed per neuron transduced.…”

Section: Resultsmentioning

confidence: 99%

“…Serial coronal or sagittal sections were cut at a thickness of 25 μm using a cryostat (Leica 9 Microsystems) as previously described. 11,21 Free-floating sections were washed with PBS and antigen retrieval was performed as described previously. 25 Mouse monoclonal anti-FMRP (5c2; 26 was used with either rabbit anti-NeuN (1:1,000; Abcam) to immunolabel neurons, or rabbit anti-S100β (1:1,000; Abcam) to label astrocytes.…”

Section: Methodsmentioning

confidence: 99%

“…9,10 In the case of FXS, FMRP is distributed in neurons throughout the brain at all ages. 11 Therefore, a gene therapy approach for treating FXS would likely necessitate widespread distribution of the transgene throughout the brain at appropriate levels and over a protracted time frame. The adeno-associated viral (AAV) vectors now in use are well-suited for meeting these requirements, 12–14 and in fact, several studies have demonstrated the efficacy of AAV-based therapies in several mouse models of neurodevelopment disorders, including Angelman Syndrome, 15 Rett Syndrome, 16–18 and tuberous sclerosis (TSC).…”

Section: Introductionmentioning

confidence: 99%

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FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

et al. 2016

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Fragile X mental retardation protein (FMRP) is absent or highly reduced in Fragile X Syndrome, a genetic disorder causing cognitive impairment and autistic behaviors. Previous proof-of-principle studies have demonstrated that restoring FMRP in the brain using viral vectors can improve pathological abnormalities in mouse models of fragile X. However, unlike small molecule drugs where the dose can readily be adjusted during treatment, viral vector–based biological therapeutic drugs present challenges in terms of achieving optimal dosing and expression levels. The objective of this study was to investigate the consequences of expressing varying levels of FMRP selectively in neurons of Fmr1 knockout and wild-type (WT) mice. A wide range of neuronal FMRP transgene levels was achieved in individual mice after intra-cerebroventricular administration of adeno-associated viral vectors coding for FMRP. In all treated knockout mice, prominent FMRP transgene expression was observed in forebrain structures, whereas lower levels were present in more caudal regions of the brain. Reduced levels of the synaptic protein PSD-95, elevated levels of the transcriptional modulator MeCP2, and abnormal motor activity, anxiety, and acoustic startle responses in Fmr1 knockout mice were fully or partially rescued after expression of FMRP at about 35–115% of WT expression, depending on the brain region examined. In the WT mouse, moderate FMRP over-expression of up to about twofold had little or no effect on PSD-95 and MeCP2 levels or on behavioral endophenotypes. In contrast, excessive over-expression in the Fmr1 knockout mouse forebrain (approximately 2.5–6-fold over WT) induced pathological motor hyperactivity and suppressed the startle response relative to WT mice. These results delineate a range of FMRP expression levels in the central nervous system that confer phenotypic improvement in fragile X mice. Collectively, these findings are pertinent to the development of long-term curative gene therapy strategies for treating Fragile X Syndrome and other neurodevelopmental disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

et al. 2016

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“…A criticism of CLIP from mixed tissue is that normalization to true input is difficult. FMRP is principally expressed in neurons, but substantial input RNA from brain tissue comes from glial cells where FMRP expression is generally very low (11,12). A CLIP signal therefore cannot be appropriately normalized to the input, making it impossible to calculate "affinity" as a surrogate of binding strength.…”

Section: If Dgkk Is the Primary Binding Target Of Fmrp Why Was It Nomentioning

confidence: 99%

Promiscuous or discriminating: Has the favored mRNA target of Fragile X Mental Retardation Protein been overlooked?

McMahon¹,

Rosbash

2016

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

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“…Within neurons, FMRP is expressed in the soma, dendrites, and spines [56]. Three RNA binding regions, two hnRNP K-homology KH domains and an RGG (arginine-glycine-glycine) box, allow FMRP to bind to the broad range of mRNAs in a selective manner [57] and transport mRNAs bound in the nucleus to the cytoplasm [58,59]. As FMRP suppresses translation of its mRNA targets [60,61], its loss leads to an "excess" of dendritic protein synthesis and increased density of dendritic spines [34, 62−65].…”

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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Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain

Cited by 82 publications

References 33 publications

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype

Promiscuous or discriminating: Has the favored mRNA target of Fragile X Mental Retardation Protein been overlooked?

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

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