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On-tissue spatial proteomics integrating MALDI-MS imaging with shotgun proteomics reveals soy consumption-induced potential candidate markers in a fragile X syndrome mouse model

ABSTRACT: Soy-based diets are associated with increased seizures and autism. Thus, there is an acute need for unbiased protein biomarker identification in Fragile X syndrome (FXS) in response to soy consumption. Herein, we present a spatial proteomics approach integrating mass spectrometry imaging (MSI) with label-free proteomics in a mouse model of FXS to map the spatial distribution and quantify the levels of proteins in the hippocampus and hypothalamus brain regions. In total, 1,250 unique peptides were spatially resolved, demonstrating the diverse array of peptidomes present in the tissue slices and the broad coverage of the strategy. A group of proteins that are known to be involved in glycolysis and synaptic transmission has been identified. The co-expression network analysis indicated that proteins in the soy-based diet group were significantly associated with metabolism and synapse modules in the Fmr1KO brain. Ultimately, this spatial proteomics work is a step toward identifying potential candidate protein markers and novel therapeutic targets for FXS

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease,Neuroblastoma

SUBMITTER: Min Ma

LAB HEAD: Lingjun Li

PROVIDER: PXD034326 | Pride | 2024-02-11

REPOSITORIES: Pride

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On-tissue spatial proteomics integrating MALDI-MS imaging with shotgun proteomics reveals soy consumption-induced biomarkers in a fragile X syndrome mouse model

Project description:Soy-based diets are associated with increased seizures and autism. Thus, there is an acute need for unbiased protein biomarker identification in Fragile X syndrome (FXS) in response to soy consumption. Herein, we present a spatial proteomics approach integrating mass spectrometry imaging (MSI) with label-free proteomics in a mouse model of FXS to map the spatial distribution and quantify the levels of proteins in the hippocampus and hypothalamus brain regions. In total, 1,004 unique peptides were spatially resolved, demonstrating the diverse array of peptidomes present on the tissue slices and the broad coverage of the strategy. A group of proteins that are known to be involved in the GABAergic system, synaptic transmission, and co-expression network analysis indicated that protein in soy group was significantly associated with metabolism and synapse modules in the Fmr1KO brain. Ultimately, this spatial proteomics work laid the ground for identifying novel therapeutic targets and biomarkers for FXS.

2022-06-02 | PXD028146 | Pride

DUX4-r exerts a neomorphic activity that depens on GTF2I in acute lymphoblastic leukemia

Project description:Translocations producing rearranged versions of the transcription factor DUX4 (DUX4-r) are one of the most frequent causes of B-cell acute lymphoblastic leukemia (B-ALL). DUX4-r retains the DNA binding domain of wt DUX4, but is truncated on the C-terminal transcription activation domain. The precise mechanism through which DUX4-r causes leukemia is unknown and no targeted therapy is currently available. We found that the rearrangement leads to both a loss and a gain of function in DUX4-r. Loss of CBP/EP300 transcriptional co-activators interaction and inability to bind and activate repressed chromatin. Gain of interaction with the transcription factor GTF2I, which redirects DUX4-r toward leukemogenic targets. Importantly, this neomorphic activity exposes an Achilles' heel whereby DUX4-r positive leukemia cells are exquisitely sensitive to GTF2I targeting, which inhibits DUX4-r leukemogenic activity. Our work elucidates the molecular mechanism through which DUX4-r causes leukemia and suggest a possible therapeutic avenue tailored to this B-ALL subtype.

2023-09-16 | PXD041273 | Pride

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

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.

2020-06-18 | PXD011630 | Pride

Proteomics analysis of ligated and recombinant human histones H3 and H4

Project description:A library of unmodified and differentially modified human histones H3 and H4 was prepared using native chemical ligation as described previously (Bartke et al., 2010; Nakamura et al., 2019). The modification status of histone H3 and H4 products was confirmed by LC-MS/MS.

2023-12-10 | PXD020773 | Pride

Inhibitory and Excitatory Synaptic Neuroadaptations in the diazepam tolerant brain

Project description:Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABAARs). BZ clinical use is hampered by tolerance and withdrawal symptoms, which include heightened seizure susceptibility, panic, and sleep disturbances. Here, we undergo a comprehensive investigation of inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Using quantitative proteomics approaches, we reveal cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways, highlighted by Ca2+/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling.

2023-10-24 | PXD041332 | Pride

Analysis of Amyloid Plaque Composition in two mouse models of Alzheimer’s disease

Project description:MALDI mass spectrometry imaging (MSI) enables label-free, spatially resolved analysis of a wide range of analytes in tissue sections. Quantitative analysis of MSI datasets is typically performed on single pixels or manually assigned regions of interest (ROI). However, many sparse, small objects such as Alzheimer’s disease (AD) brain deposits of amyloid peptides called plaques are neither single pixels nor ROI. Here, we propose a new approach to facilitate comparative computational evaluation of amyloid plaque-like objects by MSI: a fast PLAQUE PICKER tool that enables statistical evaluation of heterogeneous amyloid peptide composition. Comparing two AD mouse models, APP NL-G-F and APP PS1, we identified distinct heterogeneous plaque populations in the NL-G-F model, but only one class of plaques in the PS1 model. We propose quantitative metrics for the comparison of technical and biological MSI replicates.

2020-10-15 | PXD020824 | Pride

Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells

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

2014-10-28 | E-GEOD-62721 | biostudies-arrayexpress

FMR1 targets distinct mRNA sequence elements to regulate protein expression [Affymetrix]

Project description:Fragile-X Syndrome (FXS) is a multi-organ disease leading to mental retardation, macro-orchidism in males, and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASD). FXS is typically caused by the loss of FRAGILE X-MENTAL RETARDATION 1 (FMR1) expression, which encodes for the RNA-binding protein (RBP), FMR1 (or FMRP). We report the discovery of the RNA recognition elements (RREs), binding sites, and mRNA targets for wild-type and I304N mutant FMRP isoforms as well as its paralogs, FXR1 and FXR2. RRE frequency, ratio, and distribution determine target mRNA association with FMRP. Among highly-enriched targets, we identified many genes involved in ASD and demonstrate that FMRP can affect their protein levels in cell culture, mice, and human brain. Unexpectedly, we discovered that these targets are also dysregulated in Fmr1-/- mouse ovaries, showing signs of premature follicular overdevelopment. These results indicate that FMRP targets shared signaling pathways across different cellular contexts. As it is become increasingly appreciated that signaling pathways are important to FXS and ASD, our results here provide an invaluable molecular guide towards the pursuit of novel therapeutic targets for these devastating neurological disorders. The mRNA profile of RNA recovered from FLAG-antibody immunoprecipitated FMRP was compared to the mRNA profile of the starting lysate material.

2012-12-13 | E-GEOD-39504 | biostudies-arrayexpress

Deep Proteome profiling reveals signatures of age and sex differences in paw skin and sciatic nerve of naïve mice

Project description:The age and sex of studied animals profoundly impacts experimental outcomes in animal-based biomedical research. However, most preclinical studies in mice use a wide-spanning age range from 4 to 14 weeks and do not assess study parameters in male and female mice in parallel. This raises concerns regarding reproducibility and neglect of potentially relevant age and sex differences. Furthermore, the molecular setup of tissues in dependence of age and sex is unknown in naïve mice precluding efficient translational research. Here, we first compared two different mass spectrometric acquisition methods – DDA- and DIA-PASEF – in order to maximize the depth of proteome quantitation. We then employed an optimized workflow of quantitative proteomics based on DIA-PASEF followed by DIA-NN data analysis, and revealed significant differences in mouse paw skin and sciatic nerve (SCN) when comparing (i) male and female mice, and, in parallel, (ii) adolescent mice (4 weeks) with adult mice (14 weeks).

2022-11-29 | PXD034476 | Pride

TGF-beta/Smad2/3 signaling directly regulates several miRNAs in mouse ES Cells and early embryos

Project description:Purpose: We aimed to identify miRNAs which are induced by the Activin/Nodal effectors, P-Smad2/3, in order to further our understanding of how P-Smad2/3 controls downstream gene expression in mouse ES cells to regulate crucial biological processes. Methods: We used a previously developed Tetracycline-On (Tet-On) system (TAG1) to manipulate the levels of P-Smad2/3 in mouse ES cells and performed an Illumina deep-sequencing screen to identify miRNAs which followed the P-Smad2/3 pathway. Results: We filtered the deep-seq data to identify a list of 28 miRNAs which showed a >1.25 fold increase in response to P-Smad2/3 induction and a >1.25 fold decrease in response to P-Smad2/3 repression. Conclusions: Our study represents a comprehensive global profiling of miRNA expression in response to changes in P-Smad2/3 levels in mouse ES cells. miRNA profiles of TAG1 cells which were untreated (control), SB-431541 treated (P-Smad2/3 repressed), or Dox treated (P-Smad2/3 induced), were generated using Illumina GAII.

2013-02-11 | E-GEOD-39994 | biostudies-arrayexpress

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