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PubMed2003

Immunohistochemical analysis of protein expression after middle cerebral artery occlusion in mice.

The effect of transient focal cerebral ischemia on protein regulation was studied in mice using multiparametric immunohistochemistry. Injury was characterized by measurements of blood flow, regional protein synthesis and terminal transferase biotinylated-dUTP nick end labeling (TUNEL). The proteins studied were selected from a previously established list of differentially regulated proteins and included the GTPases dynamin, RhoB, CAS and Ran BP-1, the transcription factors Nurr1 and p-Stat 6, the protein kinase MAPK p49, the splicing factors SRPK1 and hPrp16, the cell cycle control proteins cyclin B1 and Nek2, the inflammatory proteins FKBP12 and Rag2, the cell adhesion protein paxillin and the folding protein TCP-1. Regulation patterns were diverse and comprised ipsi- and/or contralateral up- and down-regulation with or without topical association to impeding cell death. Some proteins (SRPK1, TCP-1 and Nurr1) also exhibited post-ischemic translocation from the nucleus to the cytosol. Our observations stress the importance of regional analysis for the interpretation of proteomic data, and contribute to the identification of new pathways that may be involved in the evolution of post-ischemic brain injury.

Animals↗
PubMed2002

Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes.

Linkage analyses of highly heritable electrophysiological phenotypes (EEG, ERP) that can potentially identify individuals at risk for alcoholism were performed on a large sample of families with a high density of alcohol dependence as part of the Collaborative Study on the Genetics of Alcoholism (COGA); these genetic findings are summarized. Quantitative trait loci (QTLs) were identified for several ERP characteristics (P300, N100, N400) and for the beta frequencies of the EEG where we report linkage and linkage disequilibrium at a GABA(A) receptor gene on chromosome 4. Genetic analyses of ERPs suggest that several regions of the human genome contain genetic loci related to the generation of N100, N400 and P300, which are possible candidate loci underlying the functional organization of human neuroelectric activity. The advent of genomics and proteomics and a fuller understanding of gene regulation, will open new horizons on the critical electrical events so essential for human brain function.

Adolescent↗
PubMed2002

Functional proteomics using microchannel plate detectors.

We describe the development of a novel detection system used for the functional imaging of proteins separated on electrophoretic gels. A microchannel plate detector is used here for real-time imaging of low levels of tritiated protein separated by two-dimensional (2-D) electrophoresis. The system employs radioisotope-free, low noise microchannel plates originally developed for photon counting in X-ray astronomy. Using the detector configuration described here, proteins were resolved on mini gels by either one or two-dimensional electrophoresis, transferred onto polyvinylidene difluoride membranes and directly imaged. Tritiated diisopropylfluorophosphate (DFP) was used as a selective label for the serine hydrolase class of enzymes and their distribution in the central nervous system was examined. This survey revealed approximately 24 protein spots by 2-D electrophoresis. We also investigated the relative sensitivity of these proteins towards DFP and found the peptidase, acylpeptide hydrolase to be the most sensitive brain protein towards this reagent. Using a number of different tritiated standards, it was found that the system can image as little as 0.1 Bq/mm(2) of tritium corresponding to 320 attomol of DFP labelled protein/mm(2). Moreover, the system has a wide dynamic range (>10(6)) allowing samples of high and low activity to be quantified on the same gel.

Animals↗
PubMed2004

Proteomic identification of brainstem cytosolic proteins in a neuropathic pain model.

Neuropathic pain involves co-regulation of many genes and their translational products in both peripheral and central nervous system. We used proteomics approaches to investigate expressional changes in cytosolic protein levels in rat brainstem tissues following ligation of lumbar 5 and 6 (L5, L6) spinal nerves, which generates a model of peripheral neuropathic pain (NP). Proteins from brainstem tissue homogenates of NP and SHAM animals were fractionated by two-dimensional (2-DE) gel electrophoresis to produce a high-resolution map of the brainstem soluble proteins. Proteins showing altered expression levels between NP and SHAM were selected. Isolated proteins were in-gel trypsin-digested and the resulting peptides were analyzed by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. Using the mass spectrometric data, we were able to identify 17 proteins of interest through searches of the Swiss-Prot and NCBi nonredundant protein sequence database. Several of the identified proteins, including fatty acid binding protein-brain (FABP-B), major histocompatibility complex (MHC) class 1, T-cell receptor (TCR) alpha chain, and interleukin-1 (IL-1), showed significantly higher levels in the NP rat brainstem. Proteomic analysis has identified several proteins with differential expression levels in NP as compared to SHAM. However, the function of the proteins identified is postulated; therefore, further experiments are required to determine the true role of each protein in NP.

Animals↗
PubMed2005

Mitochondrial associated metabolic proteins are selectively oxidized in A30P alpha-synuclein transgenic mice--a model of familial Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra compacta. alpha-Synuclein is strongly implicated in the pathophysiology of PD because aggregated alpha-synuclein accumulates in the brains of subjects with PD, mutations in alpha-synuclein cause familial PD, and overexpressing mutant human alpha-synuclein (A30P or A53T) causes degenerative disease in mice or drosophila. The pathophysiology of PD is poorly understood, but increasing evidence implicates mitochondrial dysfunction and oxidative stress. To understand how mutations in alpha-synuclein contribute to the pathophysiology of PD, we undertook a proteomic analysis of transgenic mice overexpressing A30P alpha-synuclein to investigate which proteins are oxidized. We observed more than twofold selective increases in specific carbonyl levels of three metabolic proteins in brains of symptomatic A30P alpha-synuclein mice: carbonic anhydrase 2 (Car2), alpha-enolase (Eno1), and lactate dehydrogenase 2 (Ldh2). Analysis of the activities of these proteins demonstrates decreased functions of these oxidatively modified proteins in brains from the A30P compared to control mice. Our findings suggest that proteins associated with impaired energy metabolism and mitochondria are particularly prone to oxidative stress associated with A30P-mutant alpha-synuclein.

Alanine↗
PubMed2026

Shared genetic architecture between major depression and intrinsic brain functional connectome organization.

BACKGROUND: Major depression (MD) is increasingly understood as a disorder characterized by widespread abnormalities in intrinsic brain functional network organization. Although both MD and brain functional connectome architecture are highly heritable, the genetic architecture underlying their relationship remains poorly characterized. METHODS: We integrated genome-wide association studies of MD with 191 ICA-based resting-state functional connectome traits to investigate their shared genetic architecture. These traits captured intrinsic connectome organization across amplitude, functional connectivity, and global connectivity domains. Cross-trait genetic analyses were used to assess pleiotropic overlap between traits. Locus-level and gene-based analyses integrating multi-omics evidence were performed to characterize the biological relevance of shared genetic signals. RESULTS: We identified significant genetic overlap between MD and 148 of 191 brain functional connectome traits. Cross-trait analyses revealed widespread shared genetic signals organized into 627 genomic loci across amplitude, functional connectivity, and global connectivity measures. Among these, 193 loci showed evidence consistent with shared causal variants based on colocalization analyses. Gene-level integration mapped these loci to 1459 protein-coding genes (390 unique genes). Multi-layer prioritization identified 17 high-confidence genes supported by convergent genomic, transcriptomic, and proteomic evidence, with enrichment in neurodevelopmental and lipid-related metabolism pathways. CONCLUSIONS: This study provides a multi-scale characterization of the shared genetic architecture between MD and intrinsic brain functional connectome organization, revealing that shared genetic signals between MD and brain functional systems are distributed across multiple functional levels and converge at the molecular level.

Connectome↗
PubMed2005

Identification of glyoxalase-I as a protein marker in a mouse model of extremes in trait anxiety.

For >15 generations, CD1 mice have been selectively and bidirectionally bred for either high-anxiety-related behavior (HAB-M) or low-anxiety-related behavior (LAB-M) on the elevated plus-maze. Independent of gender, HAB-M were more anxious than LAB-M animals in a variety of additional tests, including those reflecting risk assessment behaviors and ultrasound vocalization, with unselected CD1 "normal" control (NAB-M) and cross-mated (CM-M) mice displaying intermediate behavioral scores in most cases. Furthermore, in both the forced-swim and tail-suspension tests, LAB-M animals showed lower scores of immobility than did HAB-M and NAB-M animals, indicative of a reduced depression-like behavior. Using proteomic and microarray analyses, glyoxalase-I was identified as a protein marker, which is consistently expressed to a higher extent in LAB-M than in HAB-M mice in several brain areas. The same phenotype-dependent difference was found in red blood cells with NAB-M and CM-M animals showing intermediate expression profiles of glyoxalase-I. Additional studies will examine whether glyoxalase-I has an impact beyond that of a biomarker to predict the genetic predisposition to anxiety- and depression-like behavior.

Analysis of Variance↗
PubMed2005

Molecular biology of the blood-brain barrier.

Molecular biological investigations into the brain capillary endothelium and microvasculature, which forms the blood-brain barrier (BBB) in vivo, can provide the platform for the discovery and the molecular cloning of BBB-specific genes. Novel BBB genes can be discovered with either a genomics-based approach such as subtractive suppressive hybridization, or a proteomics approach using subtractive antibody expression cloning. BBB-specific genes are disproportionately transporter genes encoding either for carrier-mediated transporters, active efflux transporters, or receptor-mediated transporters. The discovery of new BBB transporters can lead to the development of new approaches to brain drug delivery using endogenous brain endothelial transporters.

Animals↗
PubMed2006

Comparative proteomics of cerebrospinal fluid in neuropathologically-confirmed Alzheimer's disease and non-demented elderly subjects.

OBJECTIVES: Diagnostic tests able to reveal Alzheimer's disease (AD) in living patients before cognitive ability is destroyed are urgently needed. Such tests must distinguish AD from other dementia causes, as well as differentiate subtle changes associated with normal aging from true pathology emergence. A single biomarker offering such diagnostic and prognostic capacities has eluded identification. Therefore, a valuable test for AD is likely to be based on a specific pattern of change in a set of proteins, rather than a single protein. METHODS: We examined pooled cerebrospinal fluid (CSF) samples obtained from neuropathologically-confirmed AD (n=43) and non-demented control subjects (n=43) using 2-dimensional gel electrophoresis (2DE) proteomic methodology to detect differentially expressed proteins. Proteins exhibiting expression level differences between the pools were recovered and identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. RESULTS: Five differentially-expressed proteins with potential roles in amyloid-beta metabolism and vascular and brain physiology [apolipoprotein A-1 (Apo A-1), cathepsin D (CatD), hemopexin (HPX), transthyretin (TTR), and two pigment epithelium-derived factor (PEDF) isoforms] were identified. Apo A-1, CatD and TTR were significantly reduced in the AD pool sample, while HPX and the PEDF isoforms were increased in AD CSF. DISCUSSION: These results suggest that multi-factor proteomic pattern analysis of the CSF may provide a means to diagnose and assess AD.

Aged↗
PubMed2006

Identification of brain cell death associated proteins in human post-mortem cerebrospinal fluid.

Following any form of brain insult, proteins are released from damaged tissues into the cerebrospinal fluid (CSF). This body fluid is therefore an ideal sample to use in the search for biomarkers of neurodegenerative disorders and brain damage. In this study, we used human post-mortem CSF as a model of massive brain injury and cell death for the identification of such protein markers. Pooled post-mortem CSF samples were analyzed using a protocol that combined immunoaffinity depletion of abundant CSF proteins, off-gel electrophoresis, SDS-PAGE and protein identification by LC-MS/MS. A total of 299 proteins were identified, of which 172 proteins were not previously described to be present in CSF. Of these 172 proteins, more than 75% have been described as intracellular proteins suggesting that they were released from damaged cells. Immunoblots of a number of proteins were performed on individual post-mortem CSF samples and confirmed elevated concentrations in post-mortem CSF compared to ante-mortem CSF. Interestingly, among the proteins specifically identified in the post-mortem CSF, several have been previously described as biochemical markers of brain damage.

Biomarkers↗
PubMed2006

CSF-studies in neuropsychiatric disorders.

Cerebrospinal fluid (CSF) is a clear and colourless fluid that surrounds the brain and spine. Due to the close proximity of CSF to the brain, pathological brain-processes are likely to be reflected in CSF. CSF can be obtained through lumbar puncture and is frequently performed in the differential diagnosis of neuropsychiatric disorders. Beyond clinical applications, CSF has been studied as part of different research-protocols. In this review, we will focus on CSF-analysis in Alzheimer Disease, major depression and schizophrenia. We will review both clinical applications as well as research applications in all three disorders. We will also assess new technological advances that have made it possible to study large numbers of proteins in CSF and how these advances may change CSF-analysis in the years to come.

Alzheimer Disease↗
PubMed2005

Proteomic analysis of organ-specific post-translational lysine-acetylation and -methylation in mice by use of anti-acetyllysine and -methyllysine mouse monoclonal antibodies.

Post-translational lysine-acetylation and -methylation are two major PTMs of lysine residues in proteins. Recently, we established pan-reactive anti-acetyllysine mouse mAbs, which can bind to Nepsilon-acetylated lysine residues in various contexts of amino acid sequences. In the present study, we established pan-reactive anti-methyllysine mouse mAbs comparable to the anti-acetyllysine ones. By using these anti-acetyllysine and -methyllysine antibodies, we found that the pattern of lysine-acetylated and -methylated proteins in mouse organs showed extreme variation from organ to organ. We selected brain and skeletal muscle as model cases to be further analyzed by 2-DE followed by Western blotting. In brain, alpha-tubulin at its basal level was found to be extremely acetylated; and alpha-enolase was shown to be a newly recognized possibly acetylated protein. NF-L protein, Hsc70, alpha-tubulin fragments, beta-actin, and brain-type creatine kinase were identified as putative lysine-methylated proteins in mouse brain. In skeletal muscle, lysine-methylation of alpha-actin and both lysine-acetylation and -methylation of muscle-type creatine kinase were found as novel putative lysine-modified proteins. The approach presented here might be useful to find novel disease markers and/or drug target molecules that would not be noticed by use of the traditional proteomic approach only.

Acetylation↗
PubMed2006

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims.

Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in neuronal function in the nucleus accumbens (NAc), a brain region associated with drug reinforcement. Two-dimensional gel electrophoresis was used to compare protein alterations in the NAc between cocaine overdose (COD) victims (n=10) and controls (n=10). Following image normalization, spots with significantly differential image intensities (P<0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser desorption ionization-time of flight-time of flight. A total of 1407 spots were found to be present in a minimum of five subjects per group and the intensity of 18 spots was found to be differentially abundant between the groups, leading to positive identification of 15 proteins by peptide mass fingerprinting (PMF). Of an additional 37 protein spots that were constitutively expressed, 32 proteins were positively identified by PMF. Increased proteins in COD included beta-tubulin, liprin-alpha3 and neuronal enolase, whereas decreased proteins included parvalbumin, ATP synthase beta-chain and peroxiredoxin 2. The present data provide a preliminary protein profile of COD, suggesting the involvement of novel proteins and pathways in the expression of this complex disease. Additional studies are warranted to further characterize alterations in the differentially regulated proteins. Understanding the coordinated involvement of multiple proteins in cocaine abuse provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention for drug abuse-related disorders.

Adult↗
PubMed2006

Comparative proteomics in neurodegenerative and non-neurodegenerative diseases suggest nodal point proteins in regulatory networking.

Neurodegenerative disorders (ND) encompass clinically and genetically heterogeneous diseases with considerable overlap of their clinical, neuropathological and molecular phenotype. Various causes of neurodegeneration in disease may affect eventually the same proteins within protein networks. To identify common changes in ND, we compared brain protein changes detected by 2-D electrophoresis in four mouse models for ND: (i) Parkinson's disease, (ii) Huntington's disease, (iii) prion disease Scrapie, and (iv) a model for impaired synaptic transmission. To determine specificity of these changes for ND, we extended the scope of our investigation to three neurological conditions that do not result in neurodegeneration (non-ND). We detected 12 to 216 consistent qualitative or quantitative protein changes in individual ND and non-ND models when compared to controls. Up to 36% of these proteins were found to be altered in multiple disease states (at least three) and were therefore termed nodal point proteins. Alterations in alpha B-Crystallin and splicing factor 3b (subunit 4) occurred in at least three ND but not in non-ND. In contrast, alterations in peroxiredoxin 1 and 3, astrocytic phosphoprotein PEA15, complexin 2 and aminoacylase 1 were common to both ND and non-ND. Finally, we investigated the expression pattern of the nodal point proteins in three inbred mouse strains and found different protein abundance (expression polymorphisms) in all cases. Nodal point proteins showing expression polymorphisms may be candidate proteins for disease associated modifiers.

Animals↗
PubMed2026

Extracellular Vesicles From Glioblastoma Cells Reflect 2D vs. 3D Culture Adaptation and Resistance to Temozolomide.

Glioblastoma (GBM) is an aggressive brain tumor marked by extensive heterogeneity, resistance to therapy, and dismal prognosis. Extracellular vesicles (EVs) have emerged as key players in GBM biology, mediating intercellular communication and therapy adaptation. However, the exact functions and molecular impact of EVs in GBM remain incompletely understood. In this study, we performed a comparative proteomic analysis of U87MG GBM cells grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroids following temozolomide (TMZ) treatment, alongside characterization of EVs derived from both culture systems. 3D-spheroids secreted more EVs of smaller size and exhibited a more TMZ-resistant, stem-like proteome under TMZ-induced genotoxic stress. In contrast, 2D cell cultures demonstrated greater proteome remodeling, with EVs enriched in protein families involved in DNA repair, oxidative stress adaptation, and methylation processes. Notably, several methyltransferases were decreased intracellularly but selectively retained in EVs, suggesting active sorting to influence the tumor microenvironment or modulate epigenetic states in recipient cells. EVs also carried adhesion molecules and signaling proteins linked to migration, invasion, and Wnt pathway activation, as well as metabolic enzymes connecting serine metabolism and redox control to TMZ resistance. Mapping EV and cellular proteomes onto The Cancer Genome Atlas (TCGA) dataset identified prognostic protein families associated with either poor or favorable patient outcomes. Our data demonstrate that EV cargo composition mirrors TMZ-induced phenotypic adaptation and reveals molecular mechanisms underlying therapeutic resistance. These EV-associated signatures may serve as clinically actionable biomarkers for patient stratification and offer potential targets to overcome chemoresistance in GBM.

Humans↗
PubMed2004

Proteomic analysis of human cerebral cortex in epileptic patients.

Epilepsy affects more than 0.5% of the world population and is known to be associated with a large genetic component eliciting an electrical hyperexcitability in the central nervous system. However, its pathogenic mechanisms remain poorly understood. In order to gain greater molecular incite in the pathogenesis in epilepsy, we analyzed proteomes of human cerebral cortices. Quantitative proteome analysis was used to compare signals corresponding to individual proteins between epileptic cerebral cortices from patients with temporal lobe epilepsy and age-matched non-epileptic subjects. To minimize individual variations, gender and age of the patients were matched. Changes of several spots were consistent among 6 pairs of epileptic patients and nonepileptic subjects. One of the spots was identified as the mitochondrial type Mn-superoxide dismutase (Mn-SOD) confirmed by Western blot analysis with Mn-SOD antibody and enzyme activity assay. Such results were agreeable with chemical and physical parameters given by the 2-dimensional electrophoresis (2-DE) gel. Mn-SOD was consistently down-regulated in epileptic cerebral cortices compared with those of nonepileptic subjects. Our results demonstrate a clear link between pathogenesis of epilepsy and SOD. Additionally, we identified four proteins that were consistently over-expressed in all epileptic temporal neocortices specimens and the other four proteins that were found to be expressed less than non-epileptic control subjects. These proteomic data provide cellular markers in the understanding mechanism of the epilepsy pathogenesis.

Adult↗