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At least 721 records · Page 40Linked to original sources
PubMed2002

Identification of proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing as a prefractionation step followed by two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionisation mass spectrometry.

Cerebrospinal fluid (CSF) is in close proximity to the brain and changes in the protein composition of CSF may be indicative of altered brain protein expression in neurodegenerative disorders. Analysis of brain-specific proteins in CSF is complicated by the fact that most CSF proteins are derived from the plasma and tend to obscure less abundant proteins. By adopting a prefractionation step prior to two-dimensional gel electrophoresis (2-DE), less abundant proteins are enriched and can be detected in complex proteomes such as CSF. We have developed a method in which liquid-phase isoelectric focusing (IEF) is used to prefractionate individual CSF samples; selected IEF fractions are then analysed on SYPRO-Ruby-stained 2-D gels, with final protein identification by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS). To optimise the focusing of the protein spots on the 2-D gel, the ampholyte concentration in liquid-phase IEF was minimised and the focusing time in the first dimension was increased. When comparing 2-D gels from individual prefractionated and unfractionated CSF samples it is evident that individual protein spots are larger and contain more protein after prefractionation of CSF. Generally, more protein spots were also detected in the 2-D gels from prefractionated CSF compared with direct 2-DE separations of CSF. Several proteins, including cystatin C, IgM-kappa, hemopexin, acetyl-coenzyme A carboxylase-alpha, and alpha-1-acid glycoprotein, were identified in prefractionated CSF but not in unfractionated CSF. Low abundant forms of posttranslationally modified proteins, e.g. alpha-1-acid glycoprotein and alpha-2-HS glycoprotein, can be enriched, thus better resolved and detected on the 2-D gel. Liquid-phase IEF, as a prefractionation step prior to 2-DE, reduce sample complexity, facilitate detection of less abundant protein components, increases the protein loads and the protein amount in each gel spot for MALDI-MS analysis.

Cerebrospinal Fluid Proteins↗
PubMed2005

Altered calmodulin response to light in the suprachiasmatic nucleus of PAC1 receptor knockout mice revealed by proteomic analysis.

In mammals circadian rhythms are generated by a light-entrainable oscillator located in the hypothalamic suprachiasmatic nucleus (SCN). Light signals reach the SCN via a monosynaptic neuronal pathway, the retinohypothalamic tract, originating in a subset of retinal ganglion cells. The nerve terminals of these cells contain the classical neurotransmitter glutamate and the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), and there is evidence that these two transmitters interact to mediate photoentrainment of the oscillator in the SCN. To elucidate light-provoked PACAP receptor signaling we used proteomic analysis. Wild-type mice and mice lacking the PAC1 receptor (PAC1-/-) were light stimulated at early night, and the SCN was examined for proteins that were differentially expressed using two-dimensional gel electrophoresis and identification by tandem mass spectrometry. The most striking finding, which was subsequently confirmed by Western blotting, was a significant reduction of calmodulin (CaM) in wild-type mice as compared with PAC1-/- mice. Analysis at the mRNA level by quantitative in situ hybridization histochemistry was inconclusive, indicating that a translational mechanism might be involved. The findings indicate that PAC1 receptor signaling in the SCN in response to light stimulation induces a down-regulation of CaM expression and that CaM is involved in the photic-entrainment mechanism.

Animals↗
PubMed2006

Alzheimer's disease--an interactive perspective.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss in memory and deterioration of the higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques of aggregated amyloid-beta-peptide (Abeta), intracellular neurofibrillary tangles (NFTs) that consist of hyperphosphorylated tau protein (P-tau) and a profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex. Recent data obtained via genomics, proteomics and molecular genetics, have gleaned new information with regard to the physiological and pathophysiological functions of the amyloid precursor protein (APP) and its cleavage product Abeta. This review glances over several aspects that may play a major role in the pathogenesis of AD providing an insight into APP's and Abeta's interplay with other cellular systems.

Alzheimer Disease↗
PubMed2006

Phosphoproteomic analysis of neurotrophin receptor TrkB signaling pathways in mouse brain.

1. The signaling pathways activated by trkB neurotrophin receptor have been studied in detail in cultured neurons, but little is known about the pathways activated by trkB in intact brain. TrkB is a tyrosine kinase and protein phosphorylation is a key regulatory process in the neuronal signal transduction pathways. 2. We have investigated trkB signaling in the transgenic mice overexpressing trkB in postnatal neurons (trkB.TK) using phosphoproteomics. 3. We found that several proteins are overphosphorylated on tyrosine residues in the brain of trkB.TK mice and identified some of these proteins. 4. We demonstrate that the well characterized signaling molecules mitogen-activated protein kinase (MAPK) and cyclic AMP responsive element binding protein (CREB) were phosphorylated at a higher level in the brain of trkB.TK mice when compared to the wild type littermates. Furthermore, we found that beta-actin was tyrosine phosphorylated in the brain of the transgenic mice. 5. Our results demonstrate that phosphoproteomics is a sensitive approach to investigate signaling pathways activated in mouse brain.

Animals↗
PubMed2002

Seizure-mediated accumulation of the beta subunit of Ca2+/calmodulin-dependent protein kinase II in nuclei of mouse brain cells.

We identified a 45-kDa protein by 2D electrophoresis that was enhanced following pentylenetetrazol (PTZ)-mediated seizures. Mass-spectrography of this protein revealed the beta subunit of Ca2+/calmodulin-dependent protein kinase II (CaMKIIbeta), although no evidence for increase in bulk CaMKIIbeta transcripts was obtained. Physicochemical parameters of the 45-kDa species coincided with those of the type 7 isoform of CaMKIIbeta, CaMKIIbeta7. Reverse transcription-polymerase chain reaction revealed the existence of the CaMKIIbeta7 transcript in the mouse brain, but its RNA content was small and was not elevated by PTZ injection. CaMKIIbeta7 protein is thought to be accumulated in the nuclei of brain cells by PTZ-mediated seizure via some cellular mechanisms other than transcriptional and post-transcriptional regulation.

Amino Acid Sequence↗
PubMed2003

The 14-3-3 proteins: gene, gene expression, and function.

14-3-3 proteins were discovered by Moore and Perez in the soluble extract of bovine brain. These proteins are highly abundant in the brain. In this review 14-3-3 cDNA cloning, nucleotide sequence of 14-3-3 cDNA, the structure of 14-3-3 gene and 14-3-3 gene expression, in situ hybridization of 14-3-3 mRNA in the brain, the function and regulation of 14-3-3 protein, the binding of 14-3-3 protein to other proteins, the effects of 14-3-3 protein on the binding of a protein to other proteins, and the effect on protein kinase, etc., are concisely described. From the recent rapid development of proteom technology, markedly more target proteins of 14-3-3 protein should be discovered.

14-3-3 Proteins↗
PubMed2003

Identification of a family of endocytic proteins that define a new alpha-adaptin ear-binding motif.

Endocytosis by clathrin-coated vesicles (CCVs) is an important mechanism mediating protein internalization. Here, we show that two proteins identified through a proteomics analysis of CCVs are new components of the endocytic machinery. The proteins, named NECAP (adaptin-ear-binding coat-associated protein) 1 and 2, are paralogues that display no sequence similarity or common domains with any known protein. Both are enriched in CCV coats, and further analysis of the brain-enriched isoform, NECAP 1, shows its partial localization to clathrin-coated pits and direct binding to the globular ear domain of the alpha-adaptin subunit (alpha-ear) of the adaptor protein 2 (AP-2) complex. Intriguingly, this interaction is mediated by a new motif, WVQF, that uses a distinct alpha-ear interface relative to known alpha-ear-binding partners. Disruption of this interaction blocks clathrin-mediated endocytosis. Together, our studies identify a new family of endocytic proteins that define a unique AP-2-binding motif.

Adaptor Protein Complex alpha Subunits↗
PubMed2025

ORCO: Ollivier-Ricci Curvature-Omics-an unsupervised method for analyzing robustness in biological systems.

MOTIVATION: Although recent advanced sequencing technologies have improved the resolution of genomic and proteomic data to better characterize molecular phenotypes, efficient computational tools to analyze and interpret large-scale omic data are still needed. RESULTS: To address this, we have developed a network-based bioinformatic tool called Ollivier-Ricci curvature for omics (ORCO). ORCO incorporates omics data and a network describing biological relationships between the genes or proteins and computes Ollivier-Ricci curvature (ORC) values for individual interactions. ORC is an edge-based measure that assesses network robustness. It captures functional cooperation in gene signaling using a consistent information-passing measure, which can help investigators identify therapeutic targets and key regulatory modules in biological systems. ORC has identified novel insights in multiple cancer types using genomic data and in neurodevelopmental disorders using brain imaging data. This tool is applicable to any data that can be represented as a network. AVAILABILITY AND IMPLEMENTATION: ORCO is an open-source Python package and is publicly available on GitHub at https://github.com/aksimhal/ORC-Omics.

Software↗
PubMed2006

Identification of proteins with high affinity for refolded and native PrPC.

PrPC, the cellular prion protein, is widely expressed in most tissues, including brain, muscle and the gastrointestinal tract, but its physiological role remains unclear. During propagation of transmissible spongiform encephalopathies (TSEs), prion protein is converted to the pathological isoform, PrPSc, in a process believed to be mediated by as-yet-unknown host factors. The identification of proteins associated with PrP may provide information about the biology of prions and the pathogenesis of TSEs. In the present work, we report proteins identified from brain tissue based on their ability to bind to recombinant PrP (recPrP) or form multimolecular complexes with native PrPC in the presence of cross-linkers. Immobilized his-tagged recPrP was used as an affinity matrix to isolate PrP-interacting proteins from brain homogenates of normal individuals. In parallel, PrPC-associated proteins were characterized by cross-linking and co-immunoprecipitation assays. The unknown molecules were identified by MS and the results of LC-MS/MS analysis were subsequently verified by Western blot. Both techniques resulted in identification of proteins participating in the formation of cytoskeleton and signal transduction, further supporting the hypothesis that PrP is involved in the organization and function of receptors throughout the nervous system.

Aged↗
PubMed2005

GAPs in growth factor signalling.

Approximately 2% of genes predicted by the sequenced human genome encode small GTPases and their regulators, highlighting the biological significance of regulated GTPase activity. Among the key GTPase regulators are the GTPase activating proteins (GAPs), which function to down-modulate active GTPases. Of the numerous identified GAPs, several have been implicated in signal transduction downstream of growth factors. In particular, GAPs for the Ras and Rho GTPases, which mediate a variety of receptor-transduced signals, appear to play an essential role in growth factor dependent GTPase regulation. Experimental studies of several of the GAPs have begun to elucidate mechanisms by which GAP activity is influenced by growth factor signaling, including direct phosphorylation, sub-cellular redistribution and protein degradation. Here, some of these mechanisms of GAP regulation in the context of signaling responses to growth factors are reviewed.

Brain↗
PubMed2003

Transcriptome analysis of Neisseria meningitidis during infection.

Neisseria meningitidis is the cause of septicemia and meningococcal meningitis. During the course of infection, N. meningitidis encounters multiple environments within its host, which makes rapid adaptation to environmental changes a crucial factor for neisserial pathogenicity. Employing oligonucleotide-based DNA microarrays, we analyzed the transcriptome of N. meningitidis during two key steps of meningococcal infection, i.e., the interaction with epithelial cells (HeLa cells) and endothelial cells (human brain microvascular endothelial cells). Seventy-two genes were differentially regulated after contact with epithelial cells, and 48 genes were differentially regulated after contact with endothelial cells, including a considerable proportion of well-known virulence genes. While a considerable number of genes were in concordance between bacteria adherent to both cell types, we identified several open reading frames that were differentially regulated in only one system. The data obtained with this novel approach may provide insight into the pathogenicity mechanisms of N. meningitidis and could demonstrate the importance of gene regulation on the transcriptional level during different stages of meningococcal infection.

Bacterial Adhesion↗
PubMed2026

Sugar-sweetened beverage consumption and incident depression: an exploratory multi-omics analysis of candidate biological mediators.

BACKGROUND: Depression is a leading cause of mental and physical disability globally, with its onset and progression influenced by a complex interplay of dietary, psychological, and biological factors. Recent research suggests a link between sugar-sweetened beverage (SSB) consumption and depression risk, although the potential biological pathways underlying this association remain poorly understood. METHODS: This study utilized data from 192,045 participants in the UK Biobank to examine the prospective association between SSB consumption and incident depression using Cox proportional hazards models. SSBs were defined as the sum of five beverage categories assessed via the Oxford WebQ 24-hour dietary recall. Directional consistency of the association was further examined across three external supporting datasets encompassing diverse populations: NHANES, YRBSS, and the Lianyungang Municipal School Health and Risk Factor Surveillance Study Dataset. We further investigated whether proteins, metabolites, inflammatory markers, and brain imaging phenotypes may serve as candidate mediators statistically consistent with mediation of the SSB-depression association. RESULTS: High SSB consumption was associated with an 18% higher risk of incident depression compared with non-consumers (HR = 1.18; 95% CI: 1.11-1.25), with consistent directional associations observed across external supporting datasets. A plasma proteomic signature comprising 229 proteins was constructed using elastic net regularization and was associated with an increased risk of incident depression. Exploratory mediation analyses identified 72 proteins, 36 metabolites, and 5 inflammatory markers as candidate mediators, with IL1RN showing the strongest protein-level candidate mediating effect (9.6%), and Unsaturation and neutrophil count showing the strongest metabolite- and inflammatory marker-level effects, respectively. CONCLUSIONS: This study provides preliminary evidence that proteins, metabolites, and inflammatory markers may serve as candidate mediators statistically consistent with mediation of the association between SSB consumption and incident depression. These findings are exploratory and hypothesis-generating, and future experimental studies are needed to validate these candidate pathways and assess their potential as targets for dietary interventions in depression prevention.

Humans↗
PubMed2005

Toward a neutral evolutionary model of gene expression.

We introduce a stochastic model that describes neutral changes of gene expression over evolutionary time as a compound Poisson process where evolutionary events cause changes of expression level according to a given probability distribution. The model produces simple estimators for model parameters and allows discrimination between symmetric and asymmetric distributions of evolutionary expression changes along an evolutionary lineage. Furthermore, we introduce two measures, the skewness of expression difference distributions and relative difference of evolutionary branch lengths, which are used to quantify deviation from clock-like behavior of gene expression distances. Model-based analyses of gene expression profiles in primate liver and brain samples yield the following results: (1) The majority of gene expression changes are consistent with a neutral model of evolution; (2) along evolutionary lineages, upward changes in expression are less frequent but of greater average magnitude than downward changes; and (3) the skewness measure and the relative branch length difference confirm that an acceleration of gene expression evolution occurred on the human lineage in brain but not in liver. We discuss the latter result with respect to a neutral model of transcriptome evolution and show that a small number of genes expressed in brain can account for the observed data.

Animals↗
PubMed2005

Proteomic analysis revealed a novel synaptic proline-rich membrane protein (PRR7) associated with PSD-95 and NMDA receptor.

Proteomic analyses have revealed a novel synaptic proline-rich membrane protein: PRR7 (proline rich 7), in the postsynaptic density (PSD) fraction of rat forebrain. PRR7 is 269 amino acid residues long, and displays a unique architecture, composed of a very short N-terminal extracellular region, a single membrane spanning domain, and a cytoplasmic domain possessing a proline-rich sequence and a C-terminal type-1 PDZ binding motif. A fraction of PRR7 accumulates in spines along with synapse maturation, and colocalizes with PSD-95 in a punctate pattern in rat hippocampal neural cultures. Immunoprecipitation and GST pull-down assays demonstrated that PRR7 binds to the third PDZ domain of PSD-95. In addition, the NMDA receptor subunits, NR1 and NR2B, specifically co-immunoprecipitated with PRR7. These results suggest that PRR7 is involved in modulating neural activities via interactions with the NMDA receptor and PSD-95, and PSD core formation.

Amino Acid Sequence↗
PubMed2005

Ribosome dysfunction is an early event in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and devastating disorder that is often preceded by mild cognitive impairment (MCI). In the present study, we report that in multiple cortical areas of MCI and AD subjects, there is a significant impairment in ribosome function that is not observed in the cerebellum of the same subjects. The impairment in ribosome function is associated with a decreased rate and capacity for protein synthesis, decreased ribosomal RNA and tRNA levels, and increased RNA oxidation. No alteration in the level of initiation factors was observed in the brain regions exhibiting impairments in protein synthesis. Together, these data indicate for the first time that impairments in protein synthesis may be one of the earliest neurochemical alterations in AD and directly demonstrate that the polyribosome complex is adversely affected early in the development of AD. These data have important implications for AD studies involving proteomics and studies analyzing proteolysis in AD, indicate that oxidative damage may contribute to decreased protein synthesis, and suggest a role for alterations in protein synthesis as a novel contributor to the onset and development of AD.

Aged↗
PubMed2005

Advances in stroke neuroprotection: hyperoxia and beyond.

Refinements in patient selection, improved methods of drug delivery, use of more clinically relevant animal stroke models, and the use of combination therapies that target the entire neurovascular unit make stroke neuroprotection an achievable goal. This article provides an overview of the major mechanisms of neuronal injury and the status of neuroprotective drug trials and reviews emerging strategies for treatment of acute ischemic stroke. Advances in the fields of stem cell transplantation, stroke recovery, molecular neuroimaging, genomics, and proteomics will provide new therapeutic avenues in the near future. These and other developments over the past decade raise expectations that successful stroke neuroprotection is imminent.

Brain↗
PubMed2001

Proteomics of multiprotein complexes: answering fundamental questions in neuroscience.

Proteomics tools offer new ways to analyse networks of proteins that control important neurobiological phenomena such as learning and memory. In this review, we discuss how a combined proteomic, pharmacological and genetic approach reveals that multiprotein complexes process neural information and encode memories. Simultaneous analysis of multiple proteins enables the development of new concepts and approaches for neuroscience research.

Animals↗