Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

Prieto, Marta; Folci, Alessandra; Poupon, Gwénola; Schiavi, Sara; Buzzelli, Valeria; Pronot, Marie; François, Urielle; Pousinha, Paula A.; Lattuada, N.; Abélanet, Sophie; Castagnola, Sara; Chafaï, Magda; Khayachi, Anouar; Gwizdek, Carole; Brau, Frédéric; Deval, Emmanuel; Francolini, Maura; Bardoni, Barbara; Humeau, Yann; Trezza, Viviana; Martin, Stéphane

doi:10.1038/s41467-021-21820-1

Cited by 31 publications

(28 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…About 15% of ASD cases have a genetic component such as coding sequence mutations, chromosomal rearrangements, or copy number variants [ 26 ]. For example, Fragile X syndrome is a genetic condition that results in a range of cognitive impairments and is the most common monogenic cause of autism in human patients and animal models [ 27 ]. Actually, Fragile Mental Retardation 1 (Fmr1) knock-out (KO) is one of the best preclinical genetic models associated with autistic traits.…”

Section: Different Models Of Asdmentioning

confidence: 99%

Astroglia in Autism Spectrum Disorder

Gzieło

Nikiforuk

2021

IJMS

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different intensity and may vary in types. Risk factors for ASD include disturbed brain homeostasis, genetic predispositions, or inflammation during the prenatal period caused by viruses or bacteria. The number of diagnosed cases is growing, but the main cause and mechanism leading to ASD is still uncertain. Recent findings from animal models and human cases highlight the contribution of glia to the ASD pathophysiology. It is known that glia cells are not only “gluing” neurons together but are key players participating in different processes crucial for proper brain functioning, including neurogenesis, synaptogenesis, inflammation, myelination, proper glutamate processing and many others. Despite the prerequisites for the involvement of glia in the processes related to the onset of autism, there are far too little data regarding the engagement of these cells in the development of ASD.

show abstract

Section: Different Models Of Asdmentioning

confidence: 99%

Astroglia in Autism Spectrum Disorder

Gzieło

Nikiforuk

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Most fmr1 mutations are associated with the overproduction of triplets in the 5′UTR of the gene. Few missense mutations in the fmr1 gene have been well characterized and identified as responsible for the FXS phenotype ( De Boulle et al, 1993 , Prieto et al, 2021 ; Myrick et al, 2015 ; Sitzman et al, 2018 ).…”

Section: Fmrp As Rna Binding Protein: the Double Role In Fxs And Admentioning

confidence: 99%

“…Only a few mutations have been identified in the coding region of the fmr1 gene ( De Boulle et al1993 ; Myrick et al, 2014 ) in FXS patients and all of them are localized in these two motifs, pinpointing their key role in protein functions ( Di Marino et al, 2014 ). A newly reported R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice ( Prieto et al, 2021 ).…”

Section: Fmrp As Rna Binding Protein: the Double Role In Fxs And Admentioning

confidence: 99%

FMRP-Driven Neuropathology in Autistic Spectrum Disorder and Alzheimer's disease: A Losing Game

Bleuzé

Triaca

Borreca

2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

Fragile X mental retardation protein (FMRP) is an RNA binding protein (RBP) whose absence is essentially associated to Fragile X Syndrome (FXS). As an RNA Binding Protein (RBP), FMRP is able to bind and recognize different RNA structures and the control of specific mRNAs is important for neuronal synaptic plasticity. Perturbations of this pathway have been associated with the autistic spectrum. One of the FMRP partners is the APP mRNA, the main protagonist of Alzheimer’s disease (AD), thereby regulating its protein level and metabolism. Therefore FMRP is associated to two neurodevelopmental and age-related degenerative conditions, respectively FXS and AD. Although these pathologies are characterized by different features, they have been reported to share a number of common molecular and cellular players. The aim of this review is to describe the double-edged sword of FMRP in autism and AD, possibly allowing the elucidation of key shared underlying mechanisms and neuronal circuits. As an RBP, FMRP is able to regulate APP expression promoting the production of amyloid β fragments. Indeed, FXS patients show an increase of amyloid β load, typical of other neurological disorders, such as AD, Down syndrome, Parkinson’s Disease, etc. Beyond APP dysmetabolism, the two neurodegenerative conditions share molecular targets, brain circuits and related cognitive deficits. In this review, we will point out the potential common neuropathological pattern which needs to be addressed and we will hopefully contribute to clarifying the complex phenotype of these two neurorological disorders, in order to pave the way for a novel, common disease-modifying therapy.

show abstract

“…The similarities are present even if silencing of the gene was obtained by a classical knockout (KO) approach and not by CGG expansion: the KO-1 (Bakker et al, 1994) with the neomycin cassette in the exon 5 of the Fmr1-gene and the KO-2 (Mientjes et al, 2006) that was generated from a conditional Fmr1 KO by flanking the promoter and first exon of Fmr1 with lox P site. In addition, two Fmr1 knockin (KI) model mice have been generated and they reproduced sporadic missense mutations identified in the FMR1 gene in FXS patients (Zang et al, 2009;Prieto et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Bach

Shovlin

Moriarty

et al. 2021

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

Rett syndrome (RTT) and Fragile X syndrome (FXS) are two monogenetic neurodevelopmental disorders with complex clinical presentations. RTT is caused by mutations in the Methyl-CpG binding protein 2 gene (MECP2) altering the function of its protein product MeCP2. MeCP2 modulates gene expression by binding methylated CpG dinucleotides, and by interacting with transcription factors. FXS is caused by the silencing of the FMR1 gene encoding the Fragile X Mental Retardation Protein (FMRP), a RNA binding protein involved in multiple steps of RNA metabolism, and modulating the translation of thousands of proteins including a large set of synaptic proteins. Despite differences in genetic etiology, there are overlapping features in RTT and FXS, possibly due to interactions between MeCP2 and FMRP, and to the regulation of pathways resulting in dysregulation of common molecular signaling. Furthermore, basic physiological mechanisms are regulated by these proteins and might concur to the pathophysiology of both syndromes. Considering that RTT and FXS are disorders affecting brain development, and that most of the common targets of MeCP2 and FMRP are involved in brain activity, we discuss the mechanisms of synaptic function and plasticity altered in RTT and FXS, and we consider the similarities and the differences between these two disorders.

show abstract

Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

Cited by 31 publications

References 62 publications

Astroglia in Autism Spectrum Disorder

Astroglia in Autism Spectrum Disorder

FMRP-Driven Neuropathology in Autistic Spectrum Disorder and Alzheimer's disease: A Losing Game

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Contact Info

Product

Resources

About