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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 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Amir Ata Saei

LAB HEAD: Prof. Roman A. Zubarev

PROVIDER: PXD038607 | 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 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.

2023-09-23 | PXD037675 | Pride

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

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

Gene expression of whole hippocampus 24hr post-injury in rat

Project description:Traumatic brain injury (TBI) alters and dysregulates the expression of thousands of genes in the brain. Since some of the most common problems in TBI patients are learning and memory deficits, we are studying the effects of TBI on the hippocampus, a region of the brain which is essential for learning and memory and which is known to be particularly vulnerable to TBI. We are interested in understanding how potential neuroprotective drugs alter the TBI-induced gene expression profile. The objective of this study is to elucidate and compare the differential gene expression profiles in the hippocampus of naive, sham-control, TBI and TBI plus drug treated rats. JM6, PMI-006 and E33 are three compounds with neuroprotective, anti-inflammatory and anti-oxidative effects. Our goal is to determine if different neuroprotective compounds have similar effects on common gene targets. These genes and the cell signaling pathways linked to them would then be the target of new therapeutic strategies for TBI. Rats were prepared for fluid percussion traumatic brain injury or sham injury (naÃ¯ve rats had no anesthesia and were not handled in any way and gene expression in their brains serve as baseline data) and 24 hr post-injury, hippocampi were obtained, and stored in RNA later. Total RNA was isolated, quantitified and used for Agilent microarray analysis at GenUs Biosystems. Each group of naive, sham control, TBI and TBI plus JM6, TBI plus PMI-006 and TBI plus E33 (estrogen) has three biological replicates.

2015-01-08 | E-GEOD-59645 | biostudies-arrayexpress

psiCLIP of SmB, Prp16 and Prp22 in C, C* and P spliceosomal complexes

Project description:Despite the major progress made into spliceosome mechanisms through CryoEM, a major obstacle of this approach is its inability to map the positioning of helicases on the RNA substrate. Here we present a method ‘psiCLIP’ which probes protein-RNA interactions in specific spliceosomal states. The method is based on iCLIP, but is different to previous iCLIP studies in that it is performed on step-specific spliceosomes that are prepared from in vitro splicing extracts, similarly to those prepared for CryoEM. We applied psiCLIP to SmB (C complex), Prp16 (C complex) and Prp22 (C* and P complexes), using pre-mRNA substrates based on UBC4 and ACT1. We also used ATPase deficient dominant negative (dn) mutants of Prp16 and Prp22 to determine the contribution of ATPase activity to binding patterns.

2020-03-15 | E-MTAB-8895 | biostudies-arrayexpress

System-wide profiling of drug residence time by proteome integral solubility alteration assay

Project description:Most drugs used in the clinic and drug candidates target multiple proteins, and thus detailed characterization of their efficacy targets is required. While current methods rely on quantitative measurements at thermodynamic equilibrium, kinetic parameters such as the residence time of a drug on its target provide a better proxy for efficacy in vivo. Here, we present a new Residence Time Proteome Integral Solubility Alteration (ResT-PISA) assay which provides monitoring temporal protein solubility profiles after drug removal in either cell lysate or intact cells, quantifying the lifetime of the drug-target interaction. A compressed version of the assay measures the integral under the off-curve and enables the multiplexing of binding affinity proxy measurements with residence time assessment into a single proteomic analysis. We introduce a combined scoring system for three parametric dimensions to improve prioritization of targets. By providing complementary information to other characteristics of drug-target interaction, ResT-PISA approach can become a useful tool in drug development and precision medicine.

2023-01-06 | PXD034351 | Pride

System-wide identification of enzyme substrates by thermal analysis (SIESTA)

Project description:Despite the immense importance of enzyme-substrate reactions, there is a lack of generic and unbiased tools for identifying the molecular components participating in these reactions on a cellular level. Here we developed a universal method called System-wide Identification of Enzyme Substrates by Thermal Analysis (SIESTA). The approach assumes that enzymatic post-translational modification of substrate proteins changes their thermal stability, and applies the concept of specificity to reveal potential substrates. We have already shown the applicability of SIESTA in substrate discovery for TXNRD1 and PARP10 enzymes. SIESTA successfully identified several known and novel substrate candidates for protein kinase B (AKT1). A number of putative substrates were confirmed by functional assays. Wider application of SIESTA can enhance our understanding of the role of enzymes in homeostasis and disease, open new opportunities in investigating the effect of PTMs on protein stability, and facilitate drug discovery.

2021-01-11 | PXD014445 | Pride

Microarray analysis of brain macrophage subsets and peripheral blood monocytes in traumatic brain injury

Project description:We compared arginase-1+ macrophages (macrophages were defined by flow cytometry as CD45hi CD11b+ Ly6G-) with arginase-1- brain macrophages following traumatic brain injury (TBI) by isolating these cells from YARG transgenic mice, which express YFP under the arginase-1 promoter. Both cell populations were isolated from YARG brain tissues one day following TBI. We also examined the expression profile of peripheral blood monocytes (monocytes were defined by flow cytometry as CD11bhi F4/80+) from injured YARG mice and from normal YARG mice. Peripheral blood samples were compared to TBI brain macrophages to assess gene expression changes before and after infiltration into the brain. TBI macrophage subsets were identified by using a reporter mouse strain (YARG) that expresses eYFP from an IRES inserted at the 3' end of the gene for arginase-1 (Arg1), a hallmark of alternatively activated (M2) macrophages. One day after TBI, 21Â±1.5% of ipsilateral brain macrophages expressed relatively high levels of Arg1 as detected by YFP. Gene expression analysis of Arg1+ and Arg1- brain macrophage populations revealed that these populations were distinct from either classically activated (M1) macrophages or M2 macrophages, with features of both. The Arg1+ cells differed from Arg1- cells in multiple aspects, most notably in their chemokine repertoires. Thus, the macrophage response to TBI involves recruitment of at least two major macrophage subsets. Overall, our data indicate that the macrophage response to TBI is heterogeneous and unique. Four groups (Arg1- brain macrophages post-TBI, Arg1+ brain macrophages post-TBI, normal blood monocytes, blood monocytes post-TBI) were analyzed. Four replicates of each group were analyzed for a total of 16 samples (only 3 replicates of the blood monocyte groups are included in this submission).

2013-05-01 | E-GEOD-39759 | biostudies-arrayexpress

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

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

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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

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