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Affinity AP2 Proteomics Fragile X

ABSTRACT: Fragile X syndrome (FXS), the most common inherited intellectual disability and monogenic cause of autism, results from loss of FMRP, which regulates mRNA translation essential for brain development and synaptic plasticity. FMRP has been implicated in the synaptic localization and surface expression of various membrane proteins, yet underlying mechanisms remain unclear. Here, we identified a broad dysregulation of membrane surface and associated proteins in FMRP-deficient neurons by quantitative mass spectrometry. Among them, we found increased steady-state levels of several subunits of the clathrin-adaptor protein complex 2 (AP-2), including AP2A1 and AP2B1.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Duc Duong

LAB HEAD: Gary Bassell

PROVIDER: PXD065502 | Pride | 2025-07-09

REPOSITORIES: Pride

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			Action	DRS
	liang_4ips_01.raw	Raw
	liang_4ips_01_peptidegroups.txt	Txt
	liang_4ips_01_proteins.txt	Txt
	liang_4ips_02.raw	Raw
	liang_4ips_02_peptidegroups.txt	Txt

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m6A-mediated epi-transcriptomic dysregulation underlies synaptic dysfunction in fragile X syndrome [MeRIP-seq]

Project description:N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and loss of FMRP, which has been shown to antagonize m6A readers. However, the impact of FMRP loss on transcriptome-wide m6A modifications in human FXS remains unknown. Using cortical neurons derived from healthy subjects and FXS patient-induced pluripotent stem cells, we found that FXS neurons exhibited synaptic and neuronal network defects, mirroring clinical EEG data from the same FXS patients. FMRP deficiency led to increased translation of m6A writers, resulting in transcriptome-wide hypermethylation, primarily affecting synapse-associated transcripts and increasing mRNA decay. Treatment with an m6A writer inhibitor rescued synaptic defects in FXS neurons, highlighting its therapeutic potential. Our findings uncover an epi-transcriptomic mechanism by which FMRP deficiency disrupts m6A modifications in FXS, contributing to FXS pathogenesis, and suggest a promising avenue for m6A-targeted therapies.

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m6A-mediated epi-transcriptomic dysregulation underlies synaptic dysfunction in fragile X syndrome [RNA-seq]

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Altered striatal actin - dynamics drives behavioral inflexibility in a mouse model of Fragile X syndrome

Project description:The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is Fragile X syndrome (FXS), an NDD caused by the dysfunctional RNA binding protein FMRP. Here we demonstrate how the brain region-specific composition of post-synaptic density (PSD) contributes to FXS. The FXS mouse model shows, in the striatum, an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, that is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.

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Project description:Fragile X syndrome (FXS) is caused by the absence of the fragile X mental retardation protein (FMRP). We have previously generated FXS-induced pluripotent stem cells (iPSCs) from patients' fibroblasts. In this study, we aimed at unraveling the molecular phenotype of the disease. Our data revealed aberrant regulation of neural differentiation and axon guidance genes in FXS-derived neurons, which are regulated by the RE-1 silencing transcription factor (REST). Moreover, we found REST to be elevated in FXS-derived neurons. As FMRP is involved in the microRNA (miRNA) pathway we employed microRNA-array analyses and uncovered several miRNAs dysregulated in FXS-derived neurons. We found hsa-mir-382 to be down-regulated in FXS-derived neurons, and introduction of mimic-mir-382 into these neurons was sufficient to repress REST and up-regulate its axon guidance target genes. Our data link, FMRP and REST, through the miRNA pathway, and show a new aspect in the development of FXS. Affimetrix miRNA array of two WT and two fragile X syndrome derived neurons

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Project description:Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Here we describe the establishment of an isogenic human pluripotent embryonic stem cell model of FXS. Using CRISPR/Cas9 to introduce indels in exon 3 of FMR1 and result in complete loss of FMRP (FMR1KO). We show that FMRP-deficient neurons exhibit a number of phenotypic abnormalities including neurite outgrowth and branching deficits and impaired electrophysiological network activity as measured by multi-electrode arrays. RNA-Seq and proteome analysis of FMRP-deficient neurons revealed transcriptional dysregulation in pathways related to neurodevelopment, neurotransmission, and the cell cycle.

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Project description:FXS (Fragile X Syndrome), a leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by an expansion of a CGG repeat in the 5′-UTR of the FMR1 (Fragile X Mental Retardation-1) gene. While current studies of FXS have focused on the effects of Fragile X Mental Retardation Protein (FMRP) loss in excitatory neurons, evidence suggests that GABAergic inhibitory networks are also affected in FXS. In this study, we developed a method to reproducibly derive GABAergic inhibitory neurons from multiple FXS and control human pluripotent stem cell lines (PSCs). We found that compared to control, functional assays with microelectrode arrays and immunocytochemistry suggested a developmental delay in the maturing FXS inhibitory network that involves the GABA function switch. The GABA function switch converts the GABAA channel’s role from depolarization to hyperpolarization and has profound effects on the developing brain. To investigate the cause of this delay, we analyzed 14,400 single-cell transcriptomes from FXS and control PSC-derived GABAergic neuron cultures at early and late stages of neurogenesis. Genes related to neuroblast proliferation were upregulated in FXS cells, while neuron-specific differentially expressed genes (DEGs) associated with action potential regulation, synaptic processes, and mitochondria function were downregulated in FXS cells. In addition, autism-associated genes were overrepresented in the DEGs. Our analysis of inhibitory neuron development suggests that loss of FMRP is associated with delays in the GABAergic neurogenesis and maturation. This observation suggests a novel direction for understanding the underlying disease mechanisms and may help to guide development of therapeutic interventions.

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