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Results for “brain proteomics”

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PubMed2025

Identification of Biomarkers for Right Ventricular Dysfunction in Idiopathic Dilated Cardiomyopathy Via Urinary Proteomics and Machine Learning.

BACKGROUND: Right ventricular dysfunction (RVD) is a common complication of idiopathic dilated cardiomyopathy linked to poor outcomes. However, reliable noninvasive biomarkers for RVD remain lacking. This study aimed to identify urinary proteomic markers using mass spectrometry and machine learning. METHODS: In this prospective cohort, patients with idiopathic dilated cardiomyopathy were classified by cardiac magnetic resonance imaging into groups with RVD (RV ejection fraction <45%) and without RVD groups. Baseline urine samples were profiled by data-independent acquisition mass spectrometry. Differentially expressed proteins were identified and selected by least absolute shrinkage and selection operator regression to build a diagnostic model, developed in a training set, and validated in a test set. The primary end point was a composite of cardiovascular death, heart failure rehospitalization, left ventricular assist device implantation, or heart transplantation. RESULTS: The study enrolled 147 patients with idiopathic dilated cardiomyopathy (64 with RVD, 83 without), with a median follow-up of 19.3 months. Of 3579 quantified urinary proteins, 46 were differentially expressed between groups. A 3-protein panel (RARRES1 [retinoic acid receptor responder protein 1], MVB12B [multivesicular body subunit 12B], GSK3A [glycogen synthase kinase 3 alpha]) was identified and showed excellent diagnostic accuracy (training area under the curve 0.946; validation area under the curve0.935), outperforming both NT-proBNP (N-terminal pro-brain natriuretic peptide) and tricuspid annular plane systolic excursion. The risk score derived from this panel effectively stratified patients, with the high-risk group exhibiting significantly worse outcomes than the low-risk group (hazard ratio, 3.24 [95% CI, 1.56-6.71], P=0.002). CONCLUSIONS: The urinary proteomic panel developed in this study demonstrates diagnostic and prognostic potential for identifying RVD in idiopathic dilated cardiomyopathy, providing a promising noninvasive tool for precise detection and clinical risk stratification.

Humans↗

PubMed2026

The mechanism by which long-term exposure to TDCIPP promotes cognitive impairment in 3 ×Tg-AD mice: Insights from multi-omics studies.

Tri(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate ester that has the potential to adversely affect human health. Although previous studies have closely associated TDCIPP with cognitive impairment, the underlying mechanisms remain unclear. To elucidate the neurotoxic effects of TDCIPP and its mechanistic contribution to cognitive impairment in 3 ×Tg-AD mice, a multi-omics approach incorporating proteomics, untargeted metabolomics, and 16S ribosomal RNA (rRNA) gene sequencing was employed to evaluate the impact of TDCIPP exposure on neurobehavioral function. TDCIPP exposure promoted cognitive impairment in 3 ×Tg-AD mice. Proteomic analyses revealed that this promotion is associated with disturbances in the hippocampal mitochondrial autophagy pathway. Furthermore, TDCIPP may interfere with the PINK1/Parkin-mediated mitophagy pathway at the functional level, without altering PINK1 protein abundance. Untargeted metabolomic analysis of urine samples demonstrated that TDCIPP exposure altered the metabolic profile of 3 ×Tg-AD mice, with 58 metabolites upregulated and 11 downregulated. Additionally, 16S rRNA sequencing revealed substantial modifications in gut microbiome composition following exposure to TDCIPP. Notably, significant correlations were identified between the perturbed bacterial genera and the differential metabolites. In conclusion, exposure to TDCIPP promotes cognitive impairment in 3 ×Tg-AD mice, which is associated with the interference with the PINK1/Parkin-mediated mitophagy pathway, as well as alterations in the urinary metabolome and gut microbiota. These findings suggest the potential to mitigate such cognitive impairment by targeting the microbiota-gut-brain axis.

Animals↗

PubMed2007

Peptidomics of identified neurons demonstrates a highly differentiated expression pattern of FXPRLamides in the neuroendocrine system of an insect.

FXPRLamides are insect neuropeptides that mediate such diverse functions as pheromone biosynthesis, visceral muscle contraction, and induction of diapause. Although multiple forms occur in every insect studied so far, little is known about a possible functional differentiation and/or differences in the cellular expression pattern of these messenger molecules. In this study, we performed a mass spectrometric survey of all FXPRLamide-expressing neurosecretory neurons in the CNS of Periplaneta americana. That species combines a very well characterized peptidergic system with relatively easy accessible neurosecretory cells suitable for dissection. In addition to the extensive mass spectrometric analyses of single cells, the projection of the FXPRLamide-expressing neurons was studied with three antisera specifically recognizing different FXPRLamides. The following conclusions can be drawn from this first comprehensive peptidomic approach on insect neurons. 1) A high degree of differentiation in the expression of FXPRLamides exists; not fewer then four cell types containing different sets of FXPRLamides were observed. 2) A low level of colocalization with other neuropeptides was found in these neurons. 3) A comparison with FXPRLamide-expressing neurons of other insects shows a high degree of conservation in the localization and projection of these neurons, which is not corroborated by a similar conservation of the corresponding peptide sequences. 4) Although the methods for cell identification, dissection, and sample preparation for mass spectrometry were kept as simple as possible, it was unambiguously shown that this approach is generally suitable for routine analysis of single identified neurons of insects.

Animals↗

PubMed2005

Effect of chronic morphine exposure on the synaptic plasma-membrane subproteome of rats: a quantitative protein profiling study based on isotope-coded affinity tags and liquid chromatography/mass spectrometry.

The effect of chronic morphine exposure on the synaptic plasma-membrane subproteome in rats was studied by the isotope-coded affinity tag (ICAT) method coupled with capillary reversed-phase liquid chromatography/electrospray ionization mass spectrometry and tandem mass spectrometry. ICAT-labeled tryptic peptides of synaptic membrane proteins were successfully identified using tandem mass spectrometry in conjunction with protein database searching. Several important synaptic plasma-membrane proteins displayed significant regulation changes as a result of chronic morphine exposure in vivo. In particular, an integral membrane protein Na(+)/K+ ATPase (alpha-subunit) involved in regulation of the cell membrane potential by controlling sodium and potassium ion permeability was downregulated by 39 +/- 2%. This result was in excellent agreement with the reduction in electrogenic Na+, K+ pumping due to about 40% downregulation of Na(+)/K+ ATPase alpha3-isoform in myenteric S-neurons of morphine-exposed guinea-pigs measured by others via immunohistochemistry. The decrease in the abundance of non-erythroid alpha II-spectrin in the synaptic plasma-membrane fraction was also observed, which was hypothetically associated with the breakdown of the protein due to the upregulation of the proteolytic enzyme caspase-3 upon chronic morphine exposure.

Animals↗

PubMed2005

Maximising sensitivity for detecting changes in protein expression: experimental design using minimal CyDyes.

DIGE is a powerful tool for measuring changes in protein expression between samples. Here we assess the assumptions of normality and heterogeneity of variance that underlie the univariate statistical tests routinely used to detect proteins with expression changes. Furthermore, the technical variance experienced in a multigel experiment is assessed here and found to be reproducible within- and across-sample types. Utilising the technical variance measured, a power study is completed for several "typical" fold changes in expression commonly used as thresholds by researchers. Based on this study using DeCyder, guidance is given on the number of gel replicates that are needed for the experiment to have sufficient sensitivity to detect expression changes. A two-dye system based on utilising just Cy3 and Cy5 was found to be more reproducible than the three-dye system. A power and cost-benefit analysis performed here suggests that the traditional three-dye system would use fewer resources in studies where multiple samples are compared. Technical variance was shown to encompass both experimental and analytical noise and thus is dependent on the analytical software utilised. Data is provided as a resource to the community to assess alternative software and upgrades.

Animals↗

PubMed2003

Systems biology in neuroscience: bridging genes to cognition.

Systems biology is a new branch of biology aimed at understanding biological complexity. Genomic and proteomic methods integrated with cellular and organismal analyses allow modelling of physiological processes. Progress in understanding synapse composition and new experimental and bioinformatics methods indicate the synapse is an excellent starting point for global systems biology of the brain. A neuroscience systems biology programme, organized as a consortium, is proposed.

Animals↗

PubMed2006

Use of surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) to study protein expression in a rat model of cocaine withdrawal.

Surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) is an analytical technology for proteomic analysis that combines chromatography and mass spectrometry. At present, this technology is most commonly being exploited for the simultaneous measurement of numerous proteins in serum, but has also been utilized in organ tissue, although rarely in the brain. We applied SELDI-TOF MS technology to study protein expression in the brain of rats withdrawn from repeated cocaine exposure. Our goals were to optimize sample preparation and ProteinChip Array protocols for brain tissue, to verify the reproducibility of SELDI-TOF mass spectra and to determine whether SELDI-TOF MS detects differentially expressed proteins in cocaine- versus saline-treated rats. Consequently, we have developed an optimal protocol and generated a reproducible spectral pattern with six dominant peaks in all test samples. We have detected two smaller peaks (m/z: 5179, 5030) that were significantly increased (p < 0.05) in cocaine-treated rats compared to saline-treated rats. In summary, the application of SELDI-TOF MS to the study of protein expression in a rat model of cocaine withdrawal is feasible and has the potential to generate new hypotheses.

Animals↗

PubMed2003

Molecular biology of the blood-brain barrier.

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Animals↗

PubMed2006

Morphoproteomic demonstration of constitutive nuclear factor-kappaB activation in glioblastoma multiforme with genomic correlates and therapeutic implications.

Glioblastoma multiforme (GBM) presents a major challenge to neurosurgeons, neuro-oncologists, and radiation therapists by virtue of its location with a blood-brain barrier, chemoradioresistance, highly malignant phenotype, and angiogenic potential. Because nuclear factor-kappaB (NF-kappaB) can transcriptionally activate genes leading to the synthesis of anti-apoptotic, chemoresistant, growth promoting, and angiogenic proteins; we assessed the state of activation of NF-kappaB in 6 GBM cases at diagnosis. Morphoproteomic analysis confirmed the constitutive activation of NF-kappaB by demonstrating the phosphorylation (p) and nuclear translocation of p-NF-kappaBp65 (Ser 536) in these cases. This observation coincides with (a) previous immunohistochemical findings showing nuclear translocation of total p65, (b) demonstration of NF-kappaB DNA binding activity, (c) the results of electrophoretic mobility shift assays, and (d) existing genomic data in GBM. Furthermore, such constitutive activation of the NF-kappaB pathway helps to explain some of the tumor biology and supports the incorporation of NF-kappaB pathway inhibitors into the treatment of GBM.

Adult↗

PubMed2004

Study of proteomic changes associated with healthy and tumoral murine samples in neuroblastoma by principal component analysis and classification methods.

BACKGROUND: The adrenal gland is the election organ forming primary neuroblastoma (NB) tumours, the most common extracranial solid tumours of infancy and childhood. METHODS: Samples of adrenal gland belonging to healthy and diseased nude mouse were analysed by 2D gel-electrophoresis. The resulting 2D-PAGE maps were digitized by PDQuest and investigated by principal component analysis (PCA). RESULTS: The analysis of the loadings of the first principal component (PC) permitted the evaluation of the spots characterising each class of samples. Moreover, the soft-independent model of class analogy (SIMCA) method confirmed the separation of the samples in the two classes and allowed the identification of the modelling and discriminating spots. Very good correlation was found between the data obtained by analysis of 2D maps via the commercial software PDQuest and the present PCA analysis. In both cases, the comparison between such maps showed up- and down-regulation of 84 polypeptide chains, out of a total of 700 spots detected by a fluorescent stain, Sypro Ruby. Spots that were differentially expressed between the two groups were analysed by matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and 14 of these spots were identified so far.

Animals↗

PubMed2006

Proteomic identification of a stress protein, mortalin/mthsp70/GRP75: relevance to Parkinson disease.

Functional impairment of mitochondria and proteasomes and increased oxidative damage comprise the main pathological phenotypes of Parkinson disease (PD). Using an unbiased quantitative proteomic approach, we compared nigral mitochondrial proteins of PD patients with those from age-matched controls. 119 of 842 identified proteins displayed significant differences in their relative abundance (increase/decrease) between the two groups. We confirmed that one of these, mortalin (mthsp70/GRP75, a mitochondrial stress protein), is substantially decreased in PD brains as well as in a cellular model of PD. In addition, nine candidate mortalin-binding partners were identified as potential mediators of PD pathology. Manipulations of mortalin level in dopaminergic neurons resulted in significant changes in sensitivity to PD phenotypes via pathways involving mitochondrial and proteasomal function as well as oxidative stress.

Age Factors↗

PubMed2006

A carbohydrate-binding protein, Galectin-1, promotes proliferation of adult neural stem cells.

In the subventricular zone of the adult mammalian forebrain, neural stem cells (NSCs) reside and proliferate to generate young neurons. We screened factors that promoted the proliferation of NSCs in vitro by a recently developed proteomics technique, the ProteinChip system. In this screen, we identified a soluble carbohydrate-binding protein, Galectin-1, as a candidate. We show herein that Galectin-1 is expressed in a subset of slowly dividing subventricular zone astrocytes, which includes the NSCs. Based on results from intraventricular infusion experiments and phenotypic analyses of knockout mice, we demonstrate that Galectin-1 is an endogenous factor that promotes the proliferation of NSCs in the adult brain.

Animals↗

PubMed2005

Peptidomic analysis of the larval Drosophila melanogaster central nervous system by two-dimensional capillary liquid chromatography quadrupole time-of-flight mass spectrometry.

Peptides are the largest class of signalling molecules found in animals. Nevertheless, in most proteomic studies peptides are overlooked since they literally fall through the mazes of the net. In analogy with proteomics technology, where all proteins expressed in a cell or tissue are analyzed, the peptidomic approach aims at the simultaneous visualization and identification of the whole peptidome of a cell or tissue, i.e. all expressed peptides with their post-translational modifications. In this paper we describe the analysis of the larval fruit fly central nervous system using two-dimensional capillary liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (LC/Q-TOF-MS/MS. Using the central nervous systems of only 50 larval Drosophila as starting material, we identified 38 peptides in a single analysis, 20 of which were not detected in a previous study that reported on the one-dimensional capillary LC/MS/MS analysis of the same tissue. Among the 38 sequenced peptides, some originate from precursors, such as the tachykinin and the IFamide precursor that were entirely missed in the first study. This clearly demonstrates that the two-dimensional capillary LC approach enhances the coverage of the peptidomic analysis.

Amino Acid Sequence↗

PubMed2004

Proteome analysis of human substantia nigra in Parkinson's disease.

Protein expression has been compared in human substantia nigra specimens from Parkinson's disease (PD) patients and from controls, and 44 proteins expressed in this midbrain region were identified by peptide mass fingerprinting. Among them, nine showed changes in their abundance. L and M neurofilament chains are less abundant in PD specimens, whereas peroxiredoxin II, mitochondrial complex III, ATP synthase D chain, complexin I, profilin, L-type calcium channel delta-subunit, and fatty-acid binding protein are significantly more present in PD samples than in controls. Besides the consolidated view of oxidative stress involvement in PD pathogenesis, suggested by overexpression of mitochondrial and reactive oxygen species (ROS)-scavenging proteins, these results indicate a possible potentiation mechanism of afferent signals to substantia nigra following degeneration of dopaminergic neurons.

Aged↗

PubMed2005

Antisense bcl-2 transfection up-regulates anti-apoptotic and anti-oxidant thioredoxin in neuroblastoma cells.

Antisense bcl-2 therapy combined with chemotherapy has been proved to be effective in various tumors. However, the role played by antisense bcl-2 therapy alone is not clear. In this study, we compared the apoptosis and the protein profiles of antisense bcl-2 transfected human neuroblastoma SK-N-MC cells to the control cells. Flow cytometric data indicated that antisense bcl-2 transfection did not lead to more extensive apoptosis in SK-N-MC cells (14.9 +/- 3.8%) than the control cells (10.3 +/- 2.3%). The above observation was confirmed by fluorescence microscopy using Hoechst 33258 staining. However, antisense bcl-2 induced changes in the expression of various proteins as shown by proteomic comparison, which included the up-regulation of the anti-apoptotic and anti-oxidant protein thioredoxin. By western blot validation, thioredoxin was found to be up-regulated by 2.9-folds with the corresponding down-regulation of Bcl-2 by 2.1-folds. The up-regulation of thioredoxin may be a compensating mechanism for cell survival in neuroblastoma when Bcl-2 expression is suppressed, and it may to some extent attenuate the effectiveness of antisense bcl-2 therapy.

Apoptosis↗

PubMed2005

The case for well-conducted experiments to validate statistical protocols for 2D gels: different pre-processing = different lists of significant proteins.

BACKGROUND: The proteomics literature has seen a proliferation of publications that seek to apply the rapidly improving technology of 2D gels to study various biological systems. However, there is a dearth of systematic studies that have investigated appropriate statistical approaches to analyse the data from these experiments. RESULTS: Comparison of the effects of statistical pre-processing on the results of two sample t-tests suggests that the results of 2D gel experiments and by extension the conclusions derived from these experiments are not independent of the statistical protocol used. CONCLUSIONS: This study suggests that there is a need for well-conducted validation studies to establish optimal statistical techniques to be used on such data sets.

Animals↗

PubMed2014

Combinatorial approaches for the identification of brain drug delivery targets.

The blood-brain barrier (BBB) represents a large obstacle for the treatment of central nervous system diseases. Targeting endogenous nutrient transporters that transcytose the BBB is one promising approach to selectively and noninvasively deliver a drug payload to the brain. The main limitations of the currently employed transcytosing receptors are their ubiquitous expression in the peripheral vasculature and the inherent low levels of transcytosis mediated by such systems. In this review, approaches designed to increase the repertoire of transcytosing receptors which can be targeted for the purpose of drug delivery are discussed. In particular, combinatorial protein libraries can be screened on BBB cells in vitro or in vivo to isolate targeting peptides or antibodies that can trigger transcytosis. Once these targeting reagents are discovered, the cognate BBB transcytosis system can be identified using techniques such as expression cloning or immunoprecipitation coupled with mass spectrometry. Continued technological advances in BBB genomics and proteomics, membrane protein manipulation, and in vitro BBB technology promise to further advance the capability to identify and optimize peptides and antibodies capable of mediating drug transport across the BBB.

Animals↗

PubMed2004

Mass spectrometrical analysis of phosphoprotein enriched in astrocytes of 15 kDa in mouse hippocampi.

Phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) is a small protein that was first identified as an abundant phosphoprotein in brain. PEA-15 was characterised so far at the immunochemical level and by a microsequencing attempt. In order to update characterisation of this important structure by advanced methodology unambiguously identifying proteins independent of antibody availability and specificity, we used a proteomic method for this purpose: Performing protein profiling in mouse hippocampi using two dimensional gel electrophoresis with subsequent mass spectrometrical (MS/MS) identification we detected this protein and demonstrate proteomic characterisation of PEA-15 (Q62048). This study enables further specific and unambiguous determination serving as an analytical tool.

Amino Acid Sequence↗