scholarly journals FMRP Interacts with RARα in Synaptic Retinoic Acid Signaling and Homeostatic Synaptic Plasticity

2021 ◽  
Vol 22 (12) ◽  
pp. 6579
Author(s):  
Esther Park ◽  
Anthony G. Lau ◽  
Kristin L. Arendt ◽  
Lu Chen
Keyword(s):  
Mental Retardation ◽  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Fragile X Mental Retardation ◽  
Severe Intellectual Disability ◽  
Homeostatic Synaptic Plasticity

The fragile X syndrome (FXS) is an X-chromosome-linked neurodevelopmental disorder with severe intellectual disability caused by inactivation of the fragile X mental retardation 1 (FMR1) gene and subsequent loss of the fragile X mental retardation protein (FMRP). Among the various types of abnormal synaptic function and synaptic plasticity phenotypes reported in FXS animal models, defective synaptic retinoic acid (RA) signaling and subsequent defective homeostatic plasticity have emerged as a major synaptic dysfunction. However, the mechanism underlying the defective synaptic RA signaling in the absence of FMRP is unknown. Here, we show that RARα, the RA receptor critically involved in synaptic RA signaling, directly interacts with FMRP. This interaction is enhanced in the presence of RA. Blocking the interaction between FMRP and RARα with a small peptide corresponding to the critical binding site in RARα abolishes RA-induced increases in excitatory synaptic transmission, recapitulating the phenotype seen in the Fmr1 knockout mouse. Taken together, these data suggest that not only are functional FMRP and RARα necessary for RA-dependent homeostatic synaptic plasticity, but that the interaction between these two proteins is essential for proper transcription-independent RA signaling. Our results may provide further mechanistic understanding into FXS synaptic pathophysiology.

scholarly journals The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling

2018 ◽  
Vol 10 (452) ◽  
pp. eaar4338 ◽  
Author(s):  
Zhenjie Zhang ◽  
Samuele G. Marro ◽  
Yingsha Zhang ◽  
Kristin L. Arendt ◽  
Christopher Patzke ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Retinoic Acid ◽  
Fragile X ◽  
Embryonic Stem ◽  
Synaptic Strength ◽  
Homeostatic Plasticity ◽  
Retinoic Acid Signaling ◽  
Ips Cell ◽  
Fragile X Mental Retardation ◽  
Human Neurons

Fragile X syndrome (FXS) is an X chromosome–linked disease leading to severe intellectual disabilities. FXS is caused by inactivation of the fragile X mental retardation 1 (FMR1) gene, but howFMR1inactivation induces FXS remains unclear. Using human neurons generated from control and FXS patient-derived induced pluripotent stem (iPS) cells or from embryonic stem cells carrying conditionalFMR1mutations, we show here that loss ofFMR1function specifically abolished homeostatic synaptic plasticity without affecting basal synaptic transmission. We demonstrated that, in human neurons, homeostatic plasticity induced by synaptic silencing was mediated by retinoic acid, which regulated both excitatory and inhibitory synaptic strength.FMR1inactivation impaired homeostatic plasticity by blocking retinoic acid–mediated regulation of synaptic strength. Repairing the genetic mutation in theFMR1gene in an FXS patient cell line restored fragile X mental retardation protein (FMRP) expression and fully rescued synaptic retinoic acid signaling. Thus, our study reveals a robust functional impairment caused byFMR1mutations that might contribute to neuronal dysfunction in FXS. In addition, our results suggest that FXS patient iPS cell–derived neurons might be useful for studying the mechanisms mediating functional abnormalities in FXS.

scholarly journals Altered synaptic plasticity in a mouse model of fragile X mental retardation

2002 ◽  
Vol 99 (11) ◽  
pp. 7746-7750 ◽  
Author(s):  
K. M. Huber ◽  
S. M. Gallagher ◽  
S. T. Warren ◽  
M. F. Bear
Keyword(s):  
Mental Retardation ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Fragile X ◽  
Fragile X Mental Retardation

scholarly journals An “Omic” Overview of Fragile X Syndrome

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 433
Author(s):  
Olivier Dionne ◽  
François Corbin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Medical Problems ◽  
Biochemical Alterations ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

scholarly journals Fragile X mental retardation protein and synaptic plasticity

2013 ◽  
Vol 6 (1) ◽  
pp. 15 ◽  
Author(s):  
Michael S Sidorov ◽  
Benjamin D Auerbach ◽  
Mark F Bear
Keyword(s):  
Mental Retardation ◽  
Synaptic Plasticity ◽  
Fragile X ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

scholarly journals Dynamic Association of the Fragile X Mental Retardation Protein as a Messenger Ribonucleoprotein between Microtubules and Polyribosomes

2008 ◽  
Vol 19 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Houping Wang ◽  
Jason B. Dictenberg ◽  
Li Ku ◽  
Wen Li ◽  
Gary J. Bassell ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Translational Regulation ◽  
Rna Binding ◽  
Fragile X ◽  
Synaptic Function ◽  
Dependent Manner ◽  
Fragile X Mental Retardation ◽  
Messenger Ribonucleoprotein ◽  
Mental Retardation Protein ◽  
Neuronal Processes

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein that regulates translation and plays essential roles in synaptic function. FMRP is bound to specific mRNA ligands, actively transported into neuronal processes in a microtubule-dependent manner, and associated with polyribosomes engaged in translation elongation. However, the biochemical relationship between FMRP–microtubule association and FMRP–polyribosome association remains elusive. Here, we report that although the majority of FMRP is incorporated into elongating polyribosomes in the soluble cytoplasm, microtubule-associated FMRP is predominantly retained in translationally dormant, polyribosome-free messenger ribonucleoprotein (mRNP) complexes. Interestingly, FMRP–microtubule association is increased when mRNPs are dynamically released from polyribosomes as a result of inhibiting translation initiation. Furthermore, the I304N mutant FMRP that fails to be incorporated into polyribosomes is associated with microtubules in mRNP particles and transported into neuronal dendrites in a microtubule-dependent, 3,5-dihydroxyphenylglycine-stimulated manner with similar kinetics to that of wild-type FMRP. Hence, polyribosome-free FMRP–mRNP complexes travel on microtubules and wait for activity-dependent translational derepression at the site of function. The dual participation of FMRP in dormant mRNPs and polyribosomes suggests distinct roles of FMRP in dendritic transport and translational regulation, two distinct phases that control local protein production to accommodate synaptic plasticity.

scholarly journals FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

2020 ◽  
Vol 6 (1-2) ◽  
pp. 5-19 ◽  
Author(s):  
Nicholas E. Clifton ◽  
Kerrie L. Thomas ◽  
Lawrence S. Wilkinson ◽  
Jeremy Hall ◽  
Simon Trent
Keyword(s):  
Mental Retardation ◽  
Synaptic Plasticity ◽  
Psychiatric Disorders ◽  
Fragile X ◽  
Synaptic Proteins ◽  
Interacting Protein ◽  
Fragile X Mental Retardation ◽  
Risk Variants ◽  
Mental Retardation Protein

There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (FMR1) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (CYFIP1) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.

scholarly journals Molecular Biomarkers in Fragile X Syndrome

2019 ◽  
Vol 9 (5) ◽  
pp. 96 ◽  
Author(s):  
Zafarullah ◽  
Tassone
Keyword(s):  
Clinical Trials ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Molecular Biomarkers ◽  
Synaptic Function ◽  
Primary Role ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.

Sign in / Sign up

Export Citation Format

Share Document