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TMT proteomic analysis of PFN1 iPSC-microglia

ABSTRACT: To compare the proteome between PFN1 mutant and PFN1 WT iPSC-microglia under baseline conditions

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Macrophage

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Daryl Bosco

LAB HEAD: Daryl A. Bosco

PROVIDER: PXD038943 | Pride | 2024-02-18

REPOSITORIES: Pride

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Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.

Funes Salome S Gadd Del Hayden DH Mosqueda Michelle M Zhong Jianjun J Jung Jonathan J Shankaracharya Unger Matthew M Cameron Debra D Dawes Pepper P Keagle Pamela J PJ McDonough Justin A JA Boopathy Sivakumar S Sena-Esteves Miguel M Lutz Cathleen C Skarnes William C WC Lim Elaine T ET Schafer Dorothy P DP Massi Francesca F Landers John E JE Bosco Daryl A DA

bioRxiv : the preprint server for biology 20230601

Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be fully elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs ex ...[more]

PMID: 37398081

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IP-MS of ALS-linked PFN1 variants

Project description:Dominant mutations in profilin-1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by motor neuron loss, paralysis, and death from respiratory failure. Our lab recently demonstrated that PFN1 mutant proteins are destabilized—they unfold at milder conditions during thermal and chemical denaturation. Furthermore, we and others have shown that mutant PFN1 is more prone to misfold and aggregate. This misfolding alters the protein-protein interactions of PFN1, as demonstrated by an immunoprecipitation-mass spectrometry (IP-MS) screen of wild-type and ALS-associated PFN1 variants. While ALS-associated mutants do not show loss of interaction, several variants have altered interactions with one or several formin family proteins, a group of proteins that interact with profilins to regulate actin polymerization.

2022-02-15 | PXD015602 | Pride

Proteomic interrogation of the cell envelope of Neisseria gonorrhoeae exposed to physiologically relevant environmental cues.

Project description:Gonorrhea occurs at high incidence worldwide and has a major impact on reproductive and neonatal health worldwide. Alarmingly, with each new antibiotic introduced for gonorrhea, resistance has emerged, including resistance to penicillin, tetracycline, fluoroquinolones, and recently the third-generation cephalosporins. Treatment options are currently seriously limited and the development of a gonorrhea vaccine is a critical, longterm solution to this problem. Progress on gonorrhea vaccines has been slow, however, in part due to the high number of surface molecules in Neisseria gonorrhoeae (GC) that undergo phase or antigenic variation and a lack of understanding of protective responses. Gonorrhea vaccine development can therefore benefit from a comprehensive, unbiased approach for antigen discovery. Here we identified cell envelop proteins from Neisseria gonorrhoeae exposed to physiology relevant conditions: presence of human serum, iron limitation and anaerobic growth.

2016-05-09 | PXD001944 | Pride

Characterization of I-Ab MHCII immunopeptidome eluted from control and obese (Ob/Ob) mice (2)

Project description:In Dendritic cells (DC), the MHC II eluted immunopeptidome reflects the antigenic composition of the microenvironment. Proteins are transported and processed into peptides in endosomal MHC II compartments through autophagy or phagocytosis; extracellular peptides can also directly bind MHC II proteins at the cell surface. Altogether, these mechanisms allow DC to sample both the intra and extracellular environment. With an increase in mass spectrometry sensitivity and accuracy, we can now finally tackle important questions on the nature and plasticity of the MHC-II immunopeptidome in health and disease. Presented epitopes, neoepitopes, and PTM-modified epitopes can be quantitatively and qualitatively analyzed to provide a comprehensive picture of DC role in immunosurveillance. To determine whether the redox metabolic conditions induce an altered spectrum of presented peptides, we eluted immunoaffinity-purified I-Ab from conventional dendritic cells isolated from control B6 or obese Ob/Ob mice, and analyzed MHC-II-associated peptides by LC/MS/MS using combined data-dependent (DDA) and data-independent acquisition (DIA) approaches. We analyzed the DIA data by employing a reference spectral library consisting of all peptides identified by database matching in the pool of spectra from combined DDA dataset, thus allowing a direct label-free quantitation of relative abundances between the two sample categories. The quantitative analysis of the I-Ab-eluted immunopeptidomes pinpoint important differences in peptide presentation and epitope selection in obese mice.

2021-03-21 | PXD018783 | Pride

Neisseria gonorrhoeae MlaA inversely influences gonococcal virulence and membrane vesicle production

Project description:The six-component maintenance of lipid asymmetry (Mla) system is responsible for retrograde transport of phospholipids, ensuring the barrier function of the Gram-negative cell envelope. Located within the outer membrane MlaA (VacJ) likely acts as a channel to shuttle phospholipids from the outer leaflet, bypassing the inner leaflet. In Neisseria gonorrhoeae, we previously discovered MlaA, encoded by the ngo2121 genetic locus, as a proteome-derived new vaccine and therapeutic target against this serious public health threat. Our follow-up with phenotype microarrays linked the loss of MlaA with an extensive chemical sensitivity phenome. For the current study, we investigated the role of gonococcal MlaA in bacterial physiology and pathogenicity. Quantitative proteomics were applied to cell envelopes and membrane vesicles derived from wild type and ∆mlaA bacteria to examine the alterations in protein composition induced by the loss of MlaA from the outer membrane, as well as to determine whether the abundance of known or potential virulence factors was altered in the mutant. We determined that membrane vesicles were more highly affected by the loss of MlaA than were cell envelopes, and that both cell envelopes and membrane vesicles derived from the ∆mlaA mutant were enriched with adhesins and other virulence factors.

2019-03-13 | PXD008673 | Pride

Hypothesis-generating Proteome Perturbation to Identify Molecular Modes of Drug Action: NEU-4438 and Acoziborole in the African Trypanosome

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2023-03-11 | PXD036393 | Pride

An atypical parvovirus driving chronic tubulointerstitial nephropathy and kidney fibrosis

Project description:The occurrence of a spontaneous nephropathy in laboratory mice, characterized by tubular degeneration and intranuclear inclusions, has puzzled pathologists for over four decades. While the condition takes a more severe course in immunodeficient animals suggesting an infectious cause, its etiology has remained elusive. Using an unbiased metagenomics approach, we have identified the causative agent as a novel virus, mouse kidney parvovirus (MKPV), belonging to a divergent and unclassified genus of the Parvoviridae. MKPV was found to be present in animal facilities in Australia and North America, is transmitted via the orofecal route and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathologic features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to extensive tubular degeneration and interstitial fibrosis culminating in renal failure. In summary, we identify a novel, widely distributed pathogen in laboratory mice causing significant impact on the interpretation and outcome of biomedical research based on mouse models. Additionally, we establish MKPV-induced nephropathy as a new tool for elucidating the mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

2018-09-06 | PXD010540 | Pride

A putative glucose 6-phosphate isomerase has pleiotropic effects including virulence on Acidovorax citrulli

Project description:- Identification of proteins whose expression was affected by a putative glucose 6-phosphate isomerase in Acidovorax citrulli str. KACC17005 - Shotgun proteomic analysis was used - Two strains were used with three biological replicates (total 6 samples). WT_4C: the wild-type strain. 4C: 2, a putative glucose 6-phosphate isomerase knockout mutant

2024-01-26 | PXD042560 | Pride

Comparative proteomic analysis for a bifunctional chorismate mutase/prephenate dehydratase in Acidovorax citrulli

Project description:- Identification of proteins whose expression was affected by a bifunctional chorismate mutase/prephenate dehydratase in Acidovorax citrulli str. KACC17005 - Shotgun proteomic analysis was used - Two strains were used with three biological replicates (total 6 samples). WT: the wild-type strain. 12G: a bifunctional chorismate mutase/prephenate dehydratase knockout mutant

2021-09-09 | PXD019444 | Pride

Comparative proteomic analysis for a putative 2, 3-bisphosphoglycerate-dependent phosphoglycerate mutase in Acidovorax citrulli

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2022-10-24 | PXD035156 | Pride

Quantitative proteomics of the 2016 WHO Neisseria gonorrhoeae reference strains identifies vaccine candidates and antimicrobial resistance signatures.

Project description:Neisseria gonorrhoeae is the causative agent of gonorrhea, a leading sexually transmitted disease with severe complications on reproductive health. The U.S. Centers for Disease Control and Prevention has categorized the public health threat induced by N. gonorrhoeae as “urgent”, due to the ease of transmission and the fast emergence of multi-drug resistant strains. The need for development of vaccines and understanding the underlying factors leading to antibiotic resistance is of utmost importance. The proteomic profiles of the 14 WHO N. gonorrhoeae reference strains have been compared to the WHO F reference strain using a mass spectrometry with tandem mass tags (TMT) labeling to analyze the cell envelope and the cytoplasmic fractions extracted from each strain. Identifying novel vaccine candidates and proteomic signatures for antimicrobial resistance will further our understanding of N. gonorrhoeae proteotypes, in relationship to their respective genotypes and phenotypes, and provide deep insights that will impact the development of preventive and therapeutic tools to combat gonorrhea.

2018-12-19 | PXD008412 | Pride

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