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Results for “brain proteomics”

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PubMed2006

Use of solution-IEF-fractionation leads to separation of 2673 mouse brain proteins including 255 hydrophobic structures.

Analyzing complex protein mixtures on a single gel does not allow separation of many extracted proteins. Herein, we tried a prefractionation approach and mouse brain proteins were separated on a narrow pH range ZOOM-IEF Fractionator (MicroSol-IEF device) and run on two-dimensional gel electrophoresis. A total number of 2673 protein spots including 255 hydrophobic structures were successfully analyzed by mass spectrometry. This nonsophisticated approach to increase protein identification of a brain protein extract is a step forward in neurochemistry.

Amino Acid Sequence↗

PubMedDate not supplied

A survey of canine expressed sequence tags and a display of their annotations through a flexible web-based interface.

We have initially sequenced approximately 8,000 canine expressed sequence tags (ESTs) from several complementary DNA (cDNA) libraries: testes, whole brain, and Madin-Darby canine kidney (MDCK) cells. Analysis of these sequences shows that they provide partial sequence information for about 5%-10% of the canine genes. An analysis pipeline has been created to cluster the ESTs and to map individual ESTs as well as clustered ESTs to both the human genome and the human proteome. Gene ontology (GO) terms have been assigned to the ESTs and clusters based on their top matches to the International Protein Index (IPI) set of human proteins. The data generated is stored in a MySQL relational database for analysis and display. A Web-based Perl script has been written to display the analyzed data to the scientific community.

Animals↗

PubMed2006

Calpain product of WT-CRMP2 reduces the amount of surface NR2B NMDA receptor subunit.

The brain is particularly vulnerable to ischaemia; however, neurons can become tolerant to ischaemic insult. This tolerance has been shown to involve activation of NMDA receptors, but its mechanisms have not yet been fully elucidated. Using a preconditioning protocol, we show that neurons surviving to a transient NMDA exposure become resistant to the glutamatergic agonist. Using a proteomic approach, we found that alterations of the protein pattern of NMDA-resistant neurons are restricted mainly to the five collapsin response mediator proteins (CRMPs). A sustained increase in calpain activity following NMDA treatment is responsible for the production of cleaved CRMPs. Finally, we provide evidence for the involvement of the cleaved form of WT-CRMP2 in the down-regulation of NR2B. Our data suggests that, beside their role in neuronal morphogenesis, CRMPs may contribute to neuronal plasticity.

Animals↗

PubMed2004

Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome.

RNA editing by adenosine deamination generates RNA and protein diversity through the posttranscriptional modification of single nucleotides in RNA sequences. Few mammalian A-to-I edited genes have been identified despite evidence that many more should exist. Here we identify intramolecular pairs of Alu elements as a major target for editing in the human transcriptome. An experimental demonstration in 43 genes was extended by a broader computational analysis of more than 100,000 human mRNAs. We find that 1,445 human mRNAs (1.4%) are subject to RNA editing at more than 14,500 sites, and our data further suggest that the vast majority of pre-mRNAs (greater than 85%) are targeted in introns by the editing machinery. The editing levels of Alu-containing mRNAs correlate with distance and homology between inverted repeats and vary in different tissues. Alu-mediated RNA duplexes targeted by RNA editing are formed intramolecularly, whereas editing due to intermolecular base-pairing appears to be negligible. We present evidence that these editing events can lead to the posttranscriptional creation or elimination of splice signals affecting alternatively spliced Alu-derived exons. The analysis suggests that modification of repetitive elements is a predominant activity for RNA editing with significant implications for cellular gene expression.

5' Untranslated Regions↗

PubMed2003

Epitope-targeted proteome analysis: towards a large-scale automated protein-protein-interaction mapping utilizing synthetic peptide arrays.

We describe the development of a process for the genome-wide mapping of interactions between protein domains and peptide ligands entirely based on high-throughput biochip technologies. A phage library displaying protein domains from a randomly fragmented and cloned cDNA library will be "panned" on an array of synthetic peptide ligands. After multiplexed affinity enrichment, peptide-specific phage populations will be automatically eluted, propagated, labelled and identified by hybridisation to a DNA microarray. Peptide arrays are synthesized in situ by SPOT synthesis on a planar substrate. By utilizing a commercially available library of human brain cDNA plus a set of distinct model domains cloned into T7-phage, we could show that a single panning round on an array of known peptide ligands for these model domains synthesized on a cellulose membrane can yield an enrichment of better than a factor of 1,000. This is sufficient to detect peptide-specific enrichment of Cy3(post-panning) against Cy5(pre-panning)-labelled phage DNA inserts on a cDNA microarray. Thus, the proof-of-principle of our approach could be successfully demonstrated and first interaction data are being collected.

Amino Acid Sequence↗

PubMed2004

Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain.

The sequential processing of the familial disease gene product amyloid beta precursor protein (AbetaPP) by beta- and gamma-secretases generates amyloid beta, which is considered to be the pathogenic factor of Alzheimer's disease, and the AID peptide (AbetaPP intracellular domain). The AID peptide acts as a positive regulator of apoptosis and modulates transcription and calcium release. To gain clues about the molecular mechanisms regulating the function of AbetaPP and AID, proteins interacting with the AID region of AbetaPP have been isolated using the yeast two-hybrid system. Recent evidence indicates that AbetaPP undergoes post-translational modification events in the AID region and that phosphorylation might regulate its affinity for interacting proteins. To test this possibility and to uncover AbetaPP-binding partners whose interaction depends on AbetaPP phosphorylation, we used a proteomic approach. Here we describe a protein, growth factor receptor-bound protein 2 (Grb2), that specifically binds AbetaPP, phosphorylated in Tyr(682). Furthermore, we show that this interaction is direct and that Grb2 binds to phospho-AbetaPP via its Src homology 2 region. Together with the evidence that Grb2 is in complex with AbetaPP in human brains and that these complexes are augmented in brains from Alzheimer's cases, our data indicate that Grb2 may mediate some biological and possibly pathological AbetaPP-AID function.

Adaptor Proteins, Signal Transducing↗

PubMed2026

Essence: A benchmarking-validated transformer framework for early diagnosis of Parkinson's disease using cerebrospinal fluid protein biomarkers.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The lack of objective molecular biomarkers limits early diagnosis and personalized treatment. Here, we propose Essence, a benchmarking-validated framework integrating cerebrospinal fluid (CSF) proteomics with traditional and deep learning models to identify robust protein signatures for PD. Using data from two independent cohorts, 1266 high-confidence proteins are quantified, among which 178 exhibit differential abundance between PD and healthy controls (HC). Through systematic benchmarking of ten machine learning algorithms and four neural architectures, the Transformer model consistently outperforms alternatives across multiple feature selection strategies, achieving an area under the receiver operating characteristic curve (AUC) of 1.0000 with only 35 features. Functional analyses of the top-ranked 35 proteins reveal enrichment in neuroinflammatory, synaptic, and oxidative stress-related pathways. Importantly, spatial transcriptomic profiling based on the Allen Brain Atlas shows region-specific expression of these biomarkers in PD-relevant brain structures, including the striatum, subthalamic nucleus, hippocampus, and white matter tracts. This anatomical alignment supports the functional relevance of the identified markers and highlights their potential utility in early-stage diagnosis and mechanistic understanding of PD.

Benchmarking↗

PubMed2026

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article↗

PubMed2004

New sorting nexin (SNX27) and NHERF specifically interact with the 5-HT4a receptor splice variant: roles in receptor targeting.

The 5-hydroxytryptamine type 4 receptor (5-HT4R) is involved in learning, feeding, respiratory control and gastrointestinal transit. This receptor is one of the G-protein-coupled receptors for which alternative mRNA splicing generates the most variants that differ in their C-terminal extremities. Some 5-HT4R variants (a, e and f) express canonical PDZ ligands at their C-termini. Here, we have examined whether some mouse 5-HT4R variants associate with specific sets of proteins, using a proteomic approach based on peptide-affinity chromatography, two-dimensional electrophoresis and mass spectrometry. We have identified ten proteins that interact specifically with the 5-HT4(a)R and three that only associate with the 5-HT4(e)R. Most of them are PDZ proteins. Among the proteins that associated specifically with the 5-HT4(a)R variant, NHERF greatly modified its subcellular localization. Moreover, NHERF recruited the 5-HT4(a)R to microvilli, where it localized with activated ezrin, consistent with the role of 5-HT4(a)R in cytoskeleton remodelling. The 5-HT4(a)R also interacted with both the constitutive and inducible (upon methamphetamine treatment) forms of the recently cloned sorting nexin 27 (SNX27a and b, respectively). We found that SNX27a redirected part of 5-HT4(a)R to early endosomes. The interaction of the 5-HT4R splice variants with distinct sets of PDZ proteins might specify their cellular localization as well as their signal transduction properties.

Alternative Splicing↗

PubMed2001

Deterioration of the transcriptional, splicing and elongation machinery in brain of fetal Down syndrome.

Perturbation of brain development i.e. regulation of gene expression, differentiation, growth and migration in Down Syndrome (DS) has been reported to occur early in life pointing to impairment of the complex system of transcription and or translation and indeed, altered expression of transcription factors has been reported in adult DS brain. We therefore decided to compare the transcriptional and translational machinery in cortex of brains of controls and fetuses with Down syndrome in the second trimenon of gestation. We determined a series of transcription/translation factors by 2 D-electrophoresis followed by MALDI--identification and quantification with specific software. The protooncogene C-CRK, CRK-like protein, elongation factor 1-alpha 1, elongation factor 2, elongation factor tu and two out of four spots representing PTB-associated splicing factor PSF were significantly downregulated in brain of fetal DS fetuses as compared to controls. The finding of reduced transcription and translation factors may indicate deranged protein synthesis. The underlying cause for individual reduced transcription, splicing and translation factors may be explained by chromosomal imbalance or by posttranslational modifications as e.g. phosphorylation, known to be aberrant in DS. Reduced expression of transcription factors in fetal DS during early life may be responsible or reflecting impaired brain development and deficient wiring of the brain in DS.

Brain↗

PubMed2001

Biological mechanisms of glioma invasion and potential therapeutic targets.

The current understanding of glioma biology reveals targets for anti-invasive therapy which include manipulations of extracellular matrix and receptors, growth factors and cytokines, proteases, cytoskeletal components, oncogenes and tumor suppressor genes. A better understanding of the complex regulation and the signalling molecules involved in glioma invasion is still needed in order to design new and effective treatment modalities towards invasive tumor cells. Representative and valid in vitro experimental systems and animal models of gliomas are necessary for the characterization of the invasive phenotype and further development of anti-invasive therapy. In the future, it will probably be important to move from comparative genomic modelling through protein characterization based on advanced proteomic techniques to analyse tissue samples, where the aim for gliomas should be to compare invaded and non-invaded tissue. This will hopefully render promising new therapeutic targets for gliomas.

Animals↗

PubMed2005

Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University.

BACKGROUND: Recombinant human angiostatin (rhAngiostatin) functions as a potent inhibitor of angiogenesis. This study combined rhAngiostatin with a standard chemotherapy regimen in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients had chemotherapy-naïve stage IIIB (with pleural effusion) or IV NSCLC, performance status (PS) 0 or 1, no history of bleeding, brain metastasis or requirements for anti-coagulation. Patients received carboplatin (AUC 5) intravenously and paclitaxel (175 mg/m2) intravenously day 1 + subcutaneous rhAngiostatin at either 15 mg or 60 mg twice daily. Cycles were repeated every 3 weeks, for up to six cycles. Patients without progression after completing at least four cycles were continued on maintenance rhAngiostatin until disease progression. RESULTS: Patient characteristics (n = 24) were: 16 males, median age 66 years (range 45-78), 54% PS 1, 83.3% stage IV and 62.5% adenocarcinoma. Grade 3/4 toxicities included: fatigue 47.8%, neutropenia 39.1%, dyspnea 39.1%, vascular 26.1% and infection 17.4%. The overall response rate was 39.1%, 39.1% stable disease and 21.7% progressive disease. Median time to progression was 144 days, and 1-year survival was 45.8%. CONCLUSIONS: rhAngiostatin in combination with paclitaxel and carboplatin is feasible and results in a high disease control rate in patients with advanced NSCLC.

Aged↗

PubMed2006

Tissue preparation and banking.

With the increasing application of genomic and proteomic technologies to the research of neurological and psychiatric disorders it has become imperative that the postmortem tissue utilized be of the highest quality possible. Every step of the research design, from identifying donors, acquiring sufficient information for accurate diagnosis, to assessing tissue quality has to be carefully considered. In order to obtain high-quality RNA and protein from the postmortem brain tissue a standardized system of brain collection, dissection, and storage must be employed and key ante- and postmortem factors must be considered. Reliable RNA expression and protein data can be obtained from postmortem brains with relatively long postmortem intervals (PMIs) if the agonal factors and acidosis are not severe. While pH values are correlated with RNA integrity number (RIN), a higher pH does not guarantee intact RNA. Consequently RNA integrity must be assessed for every case before it is included in a study. An analysis of anti- and postmortem factors in a large brain collection has revealed that several diagnostic groups have significantly lower pH values than other groups, however, they do not have significantly lower RIN values. Moreover, the lower pH of these groups is not entirely due to agonal factors and/or smoking, indicating that these subjects may have additional metabolic abnormalities that contribute to the lower pH values.

Autopsy↗

PubMed2003

Highly sensitive and simple fluorescence staining of proteins in sodium dodecyl sulfate-polyacrylamide-based gels by using hydrophobic tail-mediated enhancement of fluorescein luminescence.

Fluorescein has an extremely low luminescence intensity in acidic aqueous media. However, when it was bound to proteins, subsequent increase of luminescence intensity took place. Furthermore, when a hydrophobic tail, such as aliphatic hydrocarbons, was introduced to fluorescein, more dramatic increase of luminescence intensity was observed upon binding to proteins. In the present study, by utilizing this luminescence enhancement, three hydrophobic fluorescein dyes (5-dodecanoyl amino fluorescein, 5-hexadecanoyl amino fluorescein, and 5-octadecanoyl amino fluorescein) were examined as noncovalent fluorescent stains of protein bands in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Effective incorporation of the dyes to proteins in gels was accomplished either simply by adding dyes at the protein fixation step, or by treating gels with a staining solution after the fixation. The sensitivity of this staining method using the fluorescein derivatives was approximately 1 ng/band for most proteins. For some cases, protein bands containing as low as 0.1 ng were successfully visualized. In addition, the detection sensitivity showed much less protein-to-protein variation than silver staining. This new staining method was also successfully applied to two-dimensional electrophoresis of rat brain proteins. Its overall sensitivity was comparable to that of silver staining.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2026

Phosphoproteomic Analysis of Cortical Tissue from Mice Lacking Both CaMKIIα and CaMKIIβ Identifies Novel In Vivo Substrates.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in calcium signaling. Several studies have shown that mice with single Camk2a or Camk2b gene knockouts are viable, yet exhibit distinct phenotypes, whereas the double knockout of both genes is lethal. These findings indicate that each gene can have distinct roles and that they also partially compensate for each other in yet unknown essential brain functions. In order to provide insight into potential novel CaMKII functions, we performed parallel phosphoproteomic analyses on nonstimulated cortex tissues from inducible Camk2a and Camk2b double knockout (Camk2af/f;Camk2bf/f;CAG-CreESR) mice and from wild type mice. A total of 5622 phosphorylated peptides derived from 2080 proteins were identified. Phosphorylation at serine/threonine residues in 130 proteins was downregulated in the double knockout mice, including residues in 113 proteins that have not previously been identified as potential CaMKII substrates. Comparison of amino acid sequences surrounding the downregulated phosphorylation residues provided new insights into the CaMKII-substrate consensus sequences in vivo. This data set provides an important resource for future studies examining novel roles for CaMKII in the brain.

Animals↗

PubMed2005

Comparative genomics on SOX2 orthologs.

SOX2 and POU5F1 (OCT3 or OCT4) transcription factors are implicated in FGF4 expression in embryonic stem (ES) cells. SOX2, POU5F1, and FGF4 are key molecules for the integrome network in oncology and stem cell biology. SOX2 gene at human chromosome 3q26.33, SOX1 gene at 13q34, and SOX3 gene at Xq27.1 constitute a subfamily among the SOX gene family. Here, rat Sox2 and Xenopus sox2 genes were identified and characterized by using bioinformatics for comparative genomics and comparative proteomics analyses. Rat Sox2 gene, encoding a 319-aa protein, was located around the nucleotide position 73213-75621 of rat genome sequence AC123231.4. Xenopus tropicalis sox2 complete coding sequence, encoding a 311-aa protein, was derived from CR760314.1 cDNA. Rat Sox2 showed 98.4%, 97.8%, 92.2%, 88.1% and 86.8% total amino-acid identity with mouse Sox2, human SOX2, chicken sox2, Xenopus sox2 and zebrafish sox2, respectively. SOX123C domain was identified as the novel domain corresponding to the C-terminal region conserved among SOX1, SOX2 and SOX3 orthologs. Vertebrate SOX1, SOX2 and SOX3 orthologs were found consisting of HMG box and SOX123C domain. SOX9, TCF/LEF, POU2F1 and COMP1 binding sites were conserved among human SOX2 promoter, rat Sox2 promoter, and mouse Sox2 promoter. SOX2 mRNA was expressed in ES cells, fetal brain, anaplastic oligodendroglioma, rhabdomyosarcoma, and small cell lung carcinoma. Due to the pivotal role of SOX2 in the early embryogenesis, SOX2 promoter and SOX2 protein were well conserved during vertebrate evolution. This is the first report on comparative integromics analyses on the SOX2 orthologs.

Amino Acid Sequence↗

PubMed2005

Case of desmoplastic infantile ganglioglioma secreting ceruloplasmin.

Desmoplastic infantile ganglioglioma is a rare World Health Organization (WHO) grade I tumor commonly arising in early infancy and usually presenting with both solid and cystic components. We report a case of a large midline-enhancing desmoplastic infantile ganglioglioma in which newly formed cysts in communication with lateral ventricles contained highly proteinaceous fluid. Proteomic analysis of the fluid showed three proteins not normally found in cerebrospinal fluid. Immunohistochemical analysis of the tumor sample showed that the desmoplastic infantile ganglioglioma produced a high concentration of ceruloplasmin, which probably accounts for most of the 30- to 40-fold increase in protein compared with normal cerebrospinal fluid. To our knowledge, this is the first report of ceruloplasmin secretion by a brain tumor, and ongoing studies on the mechanism might yield novel approaches to reducing cyst production and protein content in an otherwise stable solid tumor.

Brain Neoplasms↗

PubMed2004

Amplification of RNA transcripts using terminal continuation.

A new methodology has been developed to amplify RNA from minute amounts of starting material. Specifically, an efficient means of second-strand (ss) cDNA synthesis using a sequence-specific 'terminal continuation' (TC) method is demonstrated. An RNA synthesis promoter is attached to the 3' and/or 5' region of cDNA utilizing the TC mechanism. The orientation of amplified RNAs is 'antisense' or a novel 'sense' orientation. TC RNA amplification is utilized for many downstream applications including gene expression profiling, cDNA microarray analysis, and cDNA library/subtraction library construction. Synthesized sense TC-amplified RNA can also be used as a template for in vitro protein translations and downstream proteomic applications. The TC RNA amplification methodology offers high sensitivity, flexibility, and throughput capabilities. A likely mechanism is that the TC primer binds preferentially to GC-rich CpG islands flanking 5' regions of DNA that contain promoter sequences. Following TC RNA amplification, a large proportion of genes can be assessed quantitatively as evidenced by bioanalysis and cDNA microarray analysis in mouse and human postmortem brain tissues.

Animals↗