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The massive solubility changes of neuronal proteins upon simulated traumatic brain injury

ABSTRACT: The molecular consequences of traumatic brain injuries or TBI are poorly understood. Here, we simulated TBI using an innovative laboratory apparatus employing a 5.1 kg dummy impact generating a ≤3,300 g-force acceleration and performed system-wide profiling of neuronal cells using Proteome Integral Solubility Alteration (PISA) assay. Dynamic impact leads to both reduction in neuron viability and massive solubility changes in the proteome. The affected proteins map not only to pathways such as cell adhesion, collagen and laminin structures, as well as response to stress, but also to other dense protein networks, such as immune response, complement and coagulation cascades. An energy absorbing material largely rescues the loss of cell viability and dampens proteome solubility changes. The cellular effects are found to be mainly due to the shockwave rather than the g-force acceleration. This study paves the way to introducing a proteome-based shock-meter as well as identifying TBI protein biomarkers and potential drug targets for prevention and intervention.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Amir Ata Saei

LAB HEAD: Prof. Roman A. Zubarev

PROVIDER: PXD037675 | Pride | 2023-09-23

REPOSITORIES: Pride

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The massive solubility changes of neuronal proteins upon simulated traumatic brain injury

Project description:The molecular consequences of traumatic brain injuries or TBI are poorly understood. Here, we simulated TBI using an innovative laboratory apparatus employing a 5.1 kg dummy impact generating a ≤3,300 g-force acceleration and performed system-wide profiling of neuronal cells using Proteome Integral Solubility Alteration (PISA) assay. Dynamic impact led to both reduction in neuron viability and massive solubility changes in the proteome. The affected proteins mapped not only to the expected pathways like cell adhesion, collagen and laminin structures, as well as response to stress, but also to other dense protein networks, such as immune response, complement and coagulation cascades. An energy absorbing material largely rescues the loss of cell viability and dampens proteome solubility changes. The cellular effects are found to be mainly due to the shockwave rather than the g-force acceleration. This study paves the way to introducing a proteome-based shock-meter as well as identifying TBI protein biomarkers and potential drug targets for primary prevention and intervention.

2023-09-23 | PXD038607 | Pride

Transcription profiling of Arabidopsis Col-0 hypocotyls time series treated with isoxaben vs untreated samples

Project description:1. Study the molecular basis of the growth acceleration observed in hypocotyl cells. We previously have observed that cell elongation takes place in two distinct phases (Refregier et al., 2004). A slow growth phase during which a thick polylamellated wall is deposited and a rapid growth phase during which cell wall polymers are extensively remodelled. In dark-grown hypocotyls the slow growth phase takes place during the first 48h after seed-imbibition synchronously in all cells. At 48h after imbibition, cells at the basis of the hypocotyl undergo a growth acceleration, this acceleration follows an acropetal gradient along the hypocotyl. In this experiment, we investigated the changes in transcript abundance that accompany this sudden increase in growth rate. 2. Study the feed-back mechanisms involved in the coordination between cellulose synthesis and the cell elongation. The inhibition of cellulose using chemical inhibitors also inhibits cell elongation. In the same study (Refregier et al., 2004), we have observed that the effect of the cellulose synthesis inhibitor isoxaben on cell elongation is different dependent on the growth stage. When applied during the slow growth phase, cells continue to elongate slowly and do not show the growth acceleration at 48h after imbibition. Surprisingly, when applied after the growth acceleration, isoxaben does not inhibit subsequent growth. In this study we compared the effects of isoxaben on the transcript profiles before and after the growth acceleration. This should inform us about the response of the hypocotyl cells to the inhibition of cellulose and should provide insights into the molecular events that underly the observed coupling between cellulose synthesis and cell elongation.

2005-01-01 | E-MEXP-195 | biostudies-arrayexpress

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ProTargetMiner: A proteome library of anticancer molecules for functional discovery

Project description:As a further development of our Functional Identification of drug Targets by Expression Proteomics (FITExP) method, a reference dataset was built of the proteomic responses of A549 human adenocarcinoma cells to 56 clinical and experimental anticancer molecules. For each molecule, a concentration was used killing 50% of the cells after 48 h. With 4557 proteins quantified across all treatments and controls, 11 orthogonal dimensions were found in factor analysis of the ProTargetMiner dataset, indicating the action of at least that many distinct cell death modalities. For convenience, the number of dimensions was reduced to three and two, thus producing a “death globe” and “death map”, respectively. As expected, molecules with similar mechanisms of action produced proteome signatures clustering together on the death globe and map. Interrogation of the dataset with partial least square modeling contrasting a given molecule against all other treatments unveiled drug targets and mechanistic proteins, even when the specific protein regulation was as subtle as a 15% change. The mechanisms of action were revealed by mapping the group of target candidates on known protein networks. The dataset allows for unique interrogation approaches, such as defining a set of co-regulated proteins. The core (“untouchable”) proteome consisting of proteins with steady expression levels unaffected by the treatments was also defined; they are found to be involved in proteasome and mRNA surveillance pathway. Finally, a list of proteins most affected by the drugs was compiled; these proteins encompass many known drug targets. The ProTargetMiner represents a resource that may be useful to the community of drug developers or scientists interested in drug action mechanisms and cell death modalities. ProTargetMiner can be easily extended to other drugs.

2019-11-01 | PXD009644 | Pride

Redox regulation of PTPN22 affects the severity of T cell dependent autoimmune inflammation

Project description:PTPN22, a modifier of T cell receptor signaling, and reactive oxygen species are major players in the regulation of chronic autoimmune diseases. As with all protein tyrosine phosphatases the activity of PTPN22 is redox regulated, but if or how such regulation can modulate inflammatory pathways in vivo is not known. To determine this, we created a mouse with a cysteine-to-serine mutation at position 129 in PTPN22 (C129S), a residue proposed to alter the redox regulatory properties of PTPN22 by forming a disulfide with the catalytic C227 residue. The C129S mutant mouse showed a stronger T cell-dependent inflammatory response due to enhanced TCR signaling and activation of T cells. Activity assays with purified proteins suggest that the functional results can be explained by an increased sensitivity to oxidation of the C129S mutated PTPN22 protein. We also observed that the disulfide of native PTPN22 can be directly reduced by the thioredoxin system, while the C129S mutant lacking this disulfide was less amenable to reductive reactivation. In conclusion, we show in the mouse that the non-catalytic C129 residue of PTPN22 modulates its redox regulatory properties, and that oxidation-prone PTPN22 leads to increased severity in the development of T cell-dependent autoimmunity.

2022-03-23 | PXD025319 | Pride

ProTargetMiner: A proteome library of anticancer molecules for functional discovery

Project description:ProTargetMiner is the first publicly available expandable proteome signature library of anticancer molecules in cancer cell lines. The compounds cluster into groups by their proteomic signatures based on their targets and mechanisms. These can be deconvoluted by orthogonal partial least square (OPLS) modeling. Using 9 molecules representing most diverse action mechanisms, deep proteome datasets were built for 3 major cancer cell lines MCF-7, RKO and A549. Combining the data from the three cell lines identified common targets and mechanisms, while also highlighting important cell-specific differences. The database can be easily extended and merged with new compound signatures. We expect ProTargetMiner to serve as a valuable chemical proteomics resource catering primarily to the cancer research community, and become a popular tool in drug discovery. This submission includes the deep proteomics datasets in MCF-7 and RKO cell lines.

2019-11-01 | PXD013134 | Pride

NCF1-dependent low production of reactive oxygen species in plasmacytoid dendritic cells exacerbates lupus

Project description:Low capacity to produce reactive oxygen species (ROS) due to mutations in neutrophil cytosolic factor 1 (NCF1/p47phox) is strongly associated with lupus development both in humans and mouse models. Here, we aim to identify the major mechanisms of the Ncf1-disease association. We found that plasmacytoid dendritic cells (pDCs), the most potent producers of type I IFNs, exacerbate pristane-induced lupus in ROS-defective Ncf1-mutant and human NCF1-339 variant carrying mice. ROS deficiency in mouse models with Ncf1 mutation or human NCF1-339 variant leads to enhanced pDC generation via the TLR7/AKT/mTOR pathway and accumulation at sites of inflammation, resulting in an increased IFNα secretion. The produced IFNα further stimulates the JAK1/STAT1 pathway, which we found is hyperreactive in ROS-deficient pDCs. This, in turn, leads to increased type I IFN signature and enhanced proinflammatory responses. Our discoveries explain the causative effect of dysfunctional Ncf1 and pathogenicity of pDCs in lupus.

2023-03-12 | PXD035964 | Pride

Comparative genomic hybridization of E.coli strains

Project description:Compare the diversity among E.coli strains with CGH

2007-12-31 | E-MEXP-1059 | biostudies-arrayexpress

Gene expression profile in rat frontal cortex during the secondary phase of trauma injury

Project description:The pathophysiology of TBI is complex and can be divided into primary damage resulting from mechanical impact and secondary damage, which comprises complex interconnecting structural, functional, cellular and molecular changes. The current study was performed to evaluate gene expression profiles in the frontal cortex at 1 month, a time at which secondary damaged can be detected, following lateral fluid percussion induced TBI (lfp-TBI) and rotational acceleration induced TBI (rot-TBI) in rats. After lfp-TBI, genes significantly expressed belong to metabolic process, immune system, cellular process, and morphogenesis. After rot-TBI, genes were related to apoptosis response, morphogenesis, angiogenesis, extracellular matrix, metabolic process, and transport and localization. Interestingly, we found that the molecular signature of secondary TBI share similar alterations to pathologies related to ischemia stroke and depression. Overlapped genes belong to immune/inflammation processes, extracellular organization, and intracellular trafficking. Their biological implications in multiple brain pathologies remain to be further examined. Nonetheless, these genes homologies may indicate that therapeutic strategies following stroke and depression may also be beneficial after trauma.

2016-12-30 | GSE67836 | GEO

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