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Results for “brain proteomics”

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At least 253 records · Page 14Linked to original sources
PubMed2006

The proteomic analysis of mouse choroid plexus secretome reveals a high protein secretion capacity of choroidal epithelial cells.

Choroid plexuses (CP) are involved in multiple functions related to their unique architecture and localization at the interface between the blood and cerebrospinal fluid compartments. These include the release by choroidal epithelial cells (CEC) of biologically active molecules, such as polypeptides, which are distributed globally to the brain. Here, we have used a proteomic approach to get an unbiased overview of the proteins that are secreted by primary cultures enriched in epithelial cells from mice CP. We identified a total of 43 proteins secreted through the classical vesicular pathway in CEC -conditioned medium. They include transport proteins, collagen subunits and other cell matrix proteins, proteases, protease inhibitors and neurotrophic factors. Treating CEC cultures with lipopolysaccharide, increased the secretion of four protein species and induced the release of two additional proteins. Our study also reveals a higher protein secretion capacity of CECs compared with other CP cells or cultured astrocytes. In conclusion, this study provides for the first time the characterization of the major proteins that are secreted by CECs. These proteins may play a critical role in neuronal growth, differentiation and function as well as in brain pathologies.

Animals↗
PubMed2004

Proteomic approach to the identification of voltage-dependent anion channel protein isoforms in guinea pig brain synaptosomes.

Voltage-dependent anion channel (VDAC) proteins are small, abundant, pore-forming proteins belonging to the eukaryotic mitochondrial porins. At least three different VDAC genes have been identified in vertebrates. VDAC proteins are known to play an essential role in cellular metabolism and in the early stages of apoptosis. A proteomic approach, consisting of two-dimensional gel electrophoresis followed by two-dimensional immunoblotting with anti-VDAC and anti-phosphotyrosine antibodies and by matrix-assisted laser desorption/ionization-time of flight mass spectrometry, was exploited to define the expression pattern of VDAC isoforms in guinea pig brain synaptosomes, both in normoxic and hypoxic conditions. In this way a total of five different VDAC isoforms were identified, as both VDAC1 and VDAC2 were detected in more than one electrophoretic spot. Moreover, VDAC isoforms selectively undergo hypoxia-induced tyrosine phosphorylation, suggesting that tyrosine phosphorylation may contribute to the modulation of VDAC protein function/conformation or interaction with other proteins in hypoxic conditions.

Animals↗
PubMed2026

Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.

With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein-disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.

Journal Article↗
PubMed2004

Proteomics in postgenomic neuroscience: the end of the beginning.

Proteomics is complementary to genomic approaches anchored in DNA and RNA. Global characterization of proteins is providing new insights into general biological structures as well as synapses, receptor complexes and other neuronal and glial features. Current challenges for proteomics of the nervous system include problems relating to sample preparation, brain complexity, limited databases and informatics tools. The combination of proteomics with other global functional genomic approaches at the levels of genome and transcriptome, together with network biology, will provide important bridges between genes, physiology and pathology.

Animals↗
PubMed2003

Overexpression of C1-tetrahydrofolate synthase in fetal Down syndrome brain.

Trisomy 21, Down Syndrome, is the most common genetic cause of human mental retardation and results from non-disjunction of chromosome 21. Several reports have been linking folate metabolism to DS and indeed, chromosome 21 even encodes for a specific folate carrier. The availability of brain tissue along with the advent of proteomics enabled us to identify and quantify C1-tetrahydrofolate synthase (THF-S), a key element in folate metabolism in brain along with other enzymes involved in C1-metabolism. Brains of controls and DS subjects at the 18th-19th week of gestation were homogenised and separated on 2 dimensional gel electrophoresis with subsequent in-gel digestion and mass spectrometrical identification and quantification with specific software. THF-S was represented by three spots, possibly representing isoforms or posttranslational modifications. Two spots were significantly, about twofold, increased in fetal DS brain: Controls [means +/- SD: (spot 1) 2.55 +/- 0.69; (spot 3) 1.39 +/- 0.86] vs. Down syndrome [means +/- SD: (spot 1) 4.25 +/- 1.63; (spot 3) 4.43 +/- 2.13]. These results were reproducible when THF-S levels were normalised versus the housekeeping protein actin and neuron specific enolase to compensate cell or neuronal loss. C1-metabolism related enzymes ribose-phosphate pyrophosphokinase I, inositol monophosphate dehydrogenase, guanidine monophosphate synthease and S-adenosylmethionine synthase, gamma form, were comparable between groups. Overexpression of this key enzyme in fetal DS brain at the early second trimester may indicate abnormal folate metabolism and may reflect folate deficiency. This may be of pathomechanistic relevance and thus extends and confirms the involvement of folate metabolism in trisomy 21.

Aminohydrolases↗
PubMedDate not supplied

Canavan disease: a monogenic trait with complex genomic interaction.

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

Amidohydrolases↗
PubMed2026

Lysine methylation is an endogenous post-translational modifications of tau protein in human brain and a modulator of aggregation propensity.

Tau protein undergoes a broad range of post-translational modifications in the brain, influencing its structure, solubility, and propensity to aggregate. This chapter presents an integrated methodological framework for characterizing tau methylation and evaluating its impact on tau biology. We describe procedures for isolating soluble and filamentous tau from post-mortem human brain tissue while preserving modifications for proteomic analysis. These approaches support precise mapping of methylation sites alongside other co-occurring modifications. To model methylation under controlled conditions, we outline protocols for recombinant tau expression, purification, and chemical reductive methylation, including radiolabeled assays for determining modification stoichiometry. We then detail biophysical assays used to assess how methylation alters tau conformation and aggregation propensity. This methodological framework supports experimentation seeking insight into mechanisms relevant to Alzheimer's disease and related tauopathies.

Humans↗
PubMed2005

Limitations of current proteomics technologies.

Application of proteomics technologies in the investigation of biological systems creates new possibilities in the elucidation of biopathomechanisms and the discovery of novel drug targets and early disease markers. A proteomic analysis involves protein separation and protein identification as well as characterization of the post-translational modifications. Proteomics has been applied in the investigation of various disorders, like neurological diseases, and the application has resulted in the detection of a large number of differences in the levels and the modifications of proteins between healthy and diseased states. However, the current proteomics technologies are still under development and show certain limitations. In this article, we discuss the major drawbacks and pitfalls of proteomics we have observed in our laboratory and in particular during the application of proteomics technologies in the investigation of the brain.

Chromatography, Liquid↗
PubMed2004

Proteomic characterization of postmortem amyloid plaques isolated by laser capture microdissection.

The presence of amyloid plaques in the brain is one of the pathological hallmarks of Alzheimer's disease (AD). We report here a comprehensive proteomic analysis of senile plaques from postmortem AD brain tissues. Senile plaques labeled with thioflavin-S were procured by laser capture microdissection, and their protein components were analyzed by liquid chromatography coupled with tandem mass spectrometry. We identified a total of 488 proteins co-isolated with the plaques, and we found multiple phosphorylation sites on the neurofilament intermediate chain, implicating the complexity and diversity of cellular processes involved in the plaque formation. More significantly, we identified 26 proteins enriched in the plaques of two AD cases by quantitative comparison with surrounding non-plaque tissues. The localization of several proteins in the plaques was further confirmed by the approach of immunohistochemistry. In addition to previously identified plaque constituents, we discovered novel association of dynein heavy chain with the plaques in human postmortem brain and in a double transgenic AD mouse model, suggesting that neuronal transport may play a role in neuritic degeneration. Overall, our results revealed for the first time the sub-proteome of amyloid plaques that is important for further studies on disease biomarker identification and molecular mechanisms of AD pathogenesis.

Aged↗
PubMed2006

An integrated map of the murine hippocampal proteome based upon five mouse strains.

With the advent of proteomics technologies it is possible to simultaneously demonstrate the expression of hundreds of proteins. The information offered by proteomics provides context-based understanding of cellular protein networks and has been proven to be a valuable approach in neuroscience studies. The mouse hippocampus has been a major target of analysis in the search for molecular correlates to neuronal information storage. Although human and rat hippocampal samples have been successfully subjected to proteomic profiling, no elaborate analysis providing the fundamental experimental basis for protein-expression studies in the mouse hippocampus has been carried out as yet. This led us to construct a master map generated from the individual hippocampal proteomes of five different mouse strains. A proteomic approach, based upon 2-DE coupled to MS (MALDI-TOF/TOF) has been chosen in an attempt to establish a comprehensive reference database of proteins expressed in the mouse hippocampus. 469 individual proteins, represented by 1156 spots displaying various functional states of the respective gene products were identified. Proteomic profiling of the hippocampus, a brain region with a pivotal role for neuronal information processing and storage may provide insight into the characteristics of proteins serving this highly sophisticated function.

Animals↗
PubMed2026

An Integrative Proteomic Approach to Reveal Altered Signaling Modules During Alzheimer's Disease Progression in PS19 Tauopathy Mice.

Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that is characterized by cognitive, functional, and behavioral impairments. These changes occur owing to the progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is associated with the dysfunction of several essential neurotransmitter systems, such as dopamine, and impaired neurotransmission. Despite the association of neurotransmitter changes within the brain and AD pathology, in-depth profiling studies on neurotransmitters and their related proteomic changes are limited. This study was conducted to profile and integrate the proteomes and neurotransmitters in seven brain regions of PS19 (Tau P301S) mice according to AD progression between 4 and 7 months. Proteomic analysis revealed significantly altered canonical pathways in various brain regions, including metabolic abnormalities. In the neurotransmitter profile, we found significant alterations in the levels of six neurotransmitters-dopamine, serotonin, homovanillic acid, norepinephrine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid-during AD progression. Using an integrative approach between proteome and neurotransmitter profiles, we found that AD progression-dependent dopamine- and serotonin-related signaling modules are closely related to neurotransmitter changes, especially in the hippocampus and cerebellum. This integrative approach could provide new signaling modules to help understand AD progression and thereby enable improved treatment and clinical outcomes.

Animals↗
PubMed2006

Unraveling age-dependent variation of the mitochondrial proteome.

Blue-native and colorless-native gel electrophoresis combined with subsequent 2D-SDS-PAGE and MALDI mass spectrometry are successfully applied for understanding the role of mitochondria in cellular dysfunction, aging, and cellular death. The partial mitochondrial proteome maps of various tissues (liver, brain, kidney, heart, and skeletal muscle) obtained from rat serve now as a database for the elucidation of age-dependent changes, including alterations in protein-protein interactions as well as in posttranslational modifications.

Aged↗
PubMed2024

Bulk serum extracellular vesicles from stressed mice show a distinct proteome and induce behavioral and molecular changes in naive mice.

Chronic stress can trigger several pathologies including mood disorders for which no clear diagnostic molecular markers have been established yet. Attractive biomarker sources are extracellular vesicles (EVs). Evs are released by cells in health and disease and contain genetic material, proteins and lipids characteristic of the cell state. Here we show that Evs recovered from the blood of animals exposed to a repeated interrupted stress protocol (RIS) have a different protein profile compared to those obtained from control animals. Proteomic analysis indicated that proteins differentially present in bulk serum Evs from stressed animals were implicated in metabolic and inflammatory pathways and several of them were previously related to psychiatric disorders. Interestingly, these serum Evs carry brain-enriched proteins including the stress-responsive neuronal protein M6a. Then, we used an in-utero electroporation strategy to selectively overexpress M6a-GFP in brain neurons and found that M6a-GFP could also be detected in bulk serum Evs suggesting a neuronal origin. Finally, to determine if these Evs could have functional consequences, we administered Evs from control and RIS animals intranasally to naïve mice. Animals receiving stress EVs showed changes in behavior and brain M6a levels similar to those observed in physically stressed animals. Such changes could therefore be attributed, or at least in part, to EV protein transfer. Altogether these findings show that EVs may participate in stress signaling and propose proteins carried by EVs as a valuable source of biomarkers for stress-induced diseases.

Animals↗
PubMed2006

Tissue heterogeneity of the mammalian mitochondrial proteome.

The functionality of the mitochondrion is primarily determined by nuclear encoded proteins. The mitochondrial functional requirements of different tissues vary from a significant biosynthetic role (liver) to a primarily energy metabolism-oriented organelle (heart). The purpose of this study was to compare the mitochondrial proteome from four different tissues of the rat, brain, liver, heart, and kidney, to provide insight into the extent of mitochondrial heterogeneity and to further characterize the overall mitochondrial proteome. Mitochondria were isolated, solubilized, digested, and subjected to quantitative liquid chromatography-mass spectroscopy. Of the 16,950 distinct peptides detected, 8,045 proteins were identified. High-confidence identification threshold was reached by 1,162 peptides, which were further analyzed. Of these 1,162 proteins, 1,149 were significantly different in content (P and q values < 0.05) between at least 2 tissues, whereas 13 were not significantly different between any tissues. Confirmation of the mitochondrial origin of proteins was determined from the literature or via NH(2)-terminal mitochondrial localization signals. With these criteria, 382 proteins in the significantly different groups were confirmed to be mitochondrial, and 493 could not be confirmed to be mitochondrial but were not definitively localized elsewhere in the cell. A total of 145 proteins were assigned to the rat mitochondrial proteome for the first time via their NH(2)-terminal mitochondrial localization signals. Among the proteins that were not significantly different between tissues, three were confirmed to be mitochondrial. Most notable of the significantly different proteins were histone family proteins and several structural proteins, including tubulin and intermediate filaments. The mitochondrial proteome from each tissue had very specific characteristics indicative of different functional emphasis. These data confirm the notion that mitochondria are tuned by the nucleus for specific functions in different tissues.

Amino Acid Sequence↗
PubMed2006

Proteomics in neurodegeneration--disease driven approaches.

Proteins as a product from genetic information execute and determine how development, growth, aging and disease factors are orchestrated within the lifetime of an organism. Differential protein expression and/or modification are always context dependent i.e. they happen within a specific context of a tissue, organ, environmental situation and individual fate. Consequently, the function/dysfunction (in a certain disease) of a specific gene cannot be predicted comprehensively by its sequence only. Genetic information can only be understood when genes and proteins are analyzed in the context of the biological system and specific networks they are involved in. In regard to neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD) many proteins are known for long years to be the cause or the consequence of the pathomechanism of the respective disease. The treatment of these neurodegenerative diseases represents a major challenge for the pharmaceutical industry, whereas the understanding of their pathogenesis is still in its infancy. With the development of several powerful techniques for proteome analysis it is now possible to investigate the expression of thousands of proteins in single cells, tissues or whole organisms at the same time. These developments opened new doors in medical sciences, and identification of cellular alterations associated with e.g. neurodegeneration will result in the identification of novel diagnostic as well as therapeutic targets. In this review, general considerations and strategies of proteomics technologies, the advantages and challenges as well as the special needs for analyzing brain tissue in the context of AD and AD are described and summarized.

Animals↗
PubMed2003

Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria.

Mitochondria are tailored to meet the metabolic and signaling needs of each cell. To explore its molecular composition, we performed a proteomic survey of mitochondria from mouse brain, heart, kidney, and liver and combined the results with existing gene annotations to produce a list of 591 mitochondrial proteins, including 163 proteins not previously associated with this organelle. The protein expression data were largely concordant with large-scale surveys of RNA abundance and both measures indicate tissue-specific differences in organelle composition. RNA expression profiles across tissues revealed networks of mitochondrial genes that share functional and regulatory mechanisms. We also determined a larger "neighborhood" of genes whose expression is closely correlated to the mitochondrial genes. The combined analysis identifies specific genes of biological interest, such as candidates for mtDNA repair enzymes, offers new insights into the biogenesis and ancestry of mammalian mitochondria, and provides a framework for understanding the organelle's contribution to human disease.

Animals↗
PubMed2006

Biomolecular interaction analysis in functional proteomics.

To understand the function of highly complex eukaryotic tissues like the human brain, in depth knowledge about cellular protein networks is required. Biomolecular interaction analysis (BIA), as a part of functional proteomics, aims to quantify interaction patterns within a protein network in detail. We used the cAMP dependent protein kinase (PKA) as a model system for the binding analysis between small natural ligands, cAMP and cAMP analogues, with their physiological interaction partner, the regulatory subunit of PKA. BIA comprises a variety of methods based on physics, biochemistry and molecular biology. Here we compared side by side real time SPR (surface plasmon resonance, Biacore), a bead based assay (AlphaScreen), a fluorescence based method (Fluorescence polarisation) and ITC (isothermal titration calorimetry). These in vitro methods were complemented by an in cell reporter assay, BRET(2) (bioluminescence resonance energy transfer), allowing to test the effects of cAMP analogues in living cells.

Animals↗