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At least 199 records · Page 11Linked to original sources
PubMed2004

Comparative proteome analysis of thalamus in MK-801-treated rats.

Two-dimensional gel-electrophoresis in combination with mass spectrometry is a powerful approach to compare protein expression in brain tissues. Using this proteomic approach, and based on the hypothesis that schizophrenia involves hypoglutamergic brain function, alterations in protein levels in the thalamus of rats treated with the N-methyl-D-aspartate (NMDA) receptor antagonist [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-iminehydrogenmaleate (MK-801), as compared to saline-treated animals, were assessed in an unbiased fashion. The rats were divided into two groups; group 1 (short-term treated) and group 2 (long-term treated). In group 1, the levels of seven proteins were increased and four proteins reduced. In group 2, the levels of six proteins were reduced. Several of the altered proteins (heat shock proteins 60 and 72, albumin, dihydropyrimidinase related protein-2, aldolase c, and malate dehydrogenase) have previously been connected to schizophrenia. Alterations of other proteins (dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex E2, guanine deaminase, alpha-enolase, aconitase, ATP-synthase and alpha-internexin), have not, to the best of our knowledge, earlier been implicated in schizophrenia pathology. Our results show the high potential of using proteomic methods for the validation of animal models of schizophrenia and to identify new proteins involved in the pathophysiological mechanisms of schizophrenia.

Animals↗
PubMed2005

Extraction and proteomic analysis of proteins from normal and multiple sclerosis postmortem brain.

In this study, a reproducible fractionation procedure was developed to reduce levels of the abundant cytoskeletal proteins that are present in normal and pathological central nervous system (CNS) tissues. The fractionation and proteomic analysis techniques employed greatly facilitated comparison of the spectrum of proteins in normal postmortem brain with proteins in samples from patients with multiple sclerosis, an inflammatory demyelinating disease in which complex changes in protein expression occur as lesions develop. This approach may be of value for the proteomic identification and quantitation of proteins which undergo disease-related changes in CNS disorders, and also for protein expression studies on normal adult and developing CNS tissues.

Aged↗
PubMed2024

Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain.

Apolipoprotein E (ApoE) polymorphisms modify the risk of Alzheimer's disease with ApoE4 strongly increasing and ApoE2 modestly decreasing risk relative to the control ApoE3. To investigate how ApoE isoforms alter risk, we measured changes in proteome homeostasis in transgenic mice expressing a human ApoE gene (isoform 2, 3, or 4). The regulation of each protein's homeostasis is observed by measuring turnover rate and abundance for that protein. We identified 4849 proteins and tested for ApoE isoform-dependent changes in the homeostatic regulation of ~2700 ontologies. In the brain, we found that ApoE4 and ApoE2 both lead to modified regulation of mitochondrial membrane proteins relative to the wild-type control ApoE3. In ApoE4 mice, lack of cohesion between mitochondrial membrane and matrix proteins suggests that dysregulation of proteasome and autophagy is reducing protein quality. In ApoE2, proteins of the mitochondrial matrix and the membrane, including oxidative phosphorylation complexes, had a similar increase in degradation which suggests coordinated replacement of the entire organelle. In the liver we did not observe these changes suggesting that the ApoE-effect on proteostasis is amplified in the brain relative to other tissues. Our findings underscore the utility of combining protein abundance and turnover rates to decipher proteome regulatory mechanisms and their potential role in biology.

Animals↗
PubMed2003

Proteomic identification of nitrated proteins in Alzheimer's disease brain.

Nitration of tyrosine in biological conditions represents a pathological event that is associated with several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease (AD). Increased levels of nitrated proteins have been reported in AD brain and CSF, demonstrating the potential involvement of reactive nitrogen species (RNS) in neurodegeneration associated with this disease. Reaction of NO with O2- leads to formation of peroxynitrite ONOO-, which following protonation, generates cytotoxic species that oxidize and nitrate proteins. Several findings suggest an important role of protein nitration in modulating the activity of key enzymes in neurodegenerative disorders, although extensive studies on specific targets of protein nitration in disease are still missing. The present investigation represents a further step in understanding the relationship between oxidative modification of protein and neuronal death in AD. We previously applied a proteomics approach to determine specific targets of protein oxidation in AD brain, by successfully coupling immunochemical detection of protein carbonyls with two-dimensional polyacrylamide gel electrophoresis and mass spectrometry analysis. In the present study, we extend our investigation of protein oxidative modification in AD brain to targets of protein nitration. The identification of six targets of protein nitration in AD brain provides evidence to the importance of oxidative stress in the progression of this dementing disease and potentially establishes a link between RNS-related protein modification and neurodegeneration.

Aged↗
PubMed2002

Proteomic analysis of protein oxidation in Alzheimer's disease brain.

There is a growing body of evidence that oxidative stress plays a major role in Alzheimer's disease (AD) pathogenesis. Identification of oxidatively altered proteins in AD is important for understanding the relationship between protein oxidation, protein aggregation and neurodegeneration. In this communication, we report a method that can be applied to study oxidative changes of individual proteins in brain. In order to analyze protein oxidation by detection of protein-bound carbonyls, cytosolic protein extracts were derivatized with 2,4-dinitrophenylhydrazine (DNPH) and then separated by two-dimensional (2-D) gel electrophoresis. After electrotransfer to polyvinylidene difluoride (PVDF) membranes, proteins were first stained with Sypro Ruby protein stain, and then the oxidized proteins were detected with anti-dinitrophenyl (DNP) antibody. About 150 proteins and more than 100 oxidized proteins were detected and quantified in both AD and control cases by 2-D image analysis. The amount of protein-bound carbonyls was decreased for six and increased for one protein in AD. The amount of protein was increased for three proteins in AD. Furthermore, the degree of oxidation was calculated as the ratio of protein-bound carbonyls to the total amount of an individual protein. Two proteins showed a significant decrease in the degree of oxidation in AD. Our results suggest that the balance of protein oxidation and degradation is altered in AD.

Aged↗
PubMed2001

Proteomic approach for the elucidation of biological defects in autism.

Proteomic-based approaches, which examine expressed proteins in tissues or cells, have great potential in the elucidation of biological defects in heterogeneous neurodevelopmental disorders such as autism. In this approach, tissue or cellular proteins from control and affected subjects are separated on two-dimensional (2-D) polyacrylamide gel electrophoresis, and those proteins that show marked changes in the concentration between control and affected subjects are identified by mass spectroscopy. This method has been successfully applied in the elucidation of the molecular biological defect in classic late-infantile neuronal ceroid lipofuscinosis (Sleat et al., 1997). Unlike the classical methods of genome-wide screening for chromosomal localization followed by positional cloning, the proteomic approach requires limited number of tissue samples and the study can be completed in a relatively short time. Currently, these methods are available for relatively abundant proteins and generally are not applicable for hydrophobic proteins because 2-D gel electrophoresis is not very effective in the analysis of hydrophobic proteins. The genetic defect results in either total loss of proteins or changes in molecular weight and/or isoelectric point will be detectable by the proteomic method. Because autism is a neurogenetic disorder, brain is the tissue of choice for proteomic study. For an oligogenic disorder such as autism, at least some of the aberrant (genes) proteins may be identified by this technology.

Autistic Disorder↗
PubMed2026

Metaproteomic profiling reveals viral proteins and associated host proteomic alterations in glioblastoma.

Glioblastoma (GB) is a WHO grade 4 brain cancer with dismal prognosis, yet its aetiology remains poorly defined. Although viral involvement has been proposed, findings across studies remain inconsistent, reflecting inherent limitations of individual technologies and cohort size. Here we applied metaproteomic profiling to a publicly available GB proteome dataset (12 control, 21 adjacent, 159 tumour) and an independent cohort of 81 samples (37 control, 44 tumour) to detect viral proteins in tumour and controls tissues. Across cohorts, we detected viral proteins from diverse species, with human herpesviruses (HHV-1, 2, and 8) more frequently detected in GB tumours compared with control tissues. Analysis of the host tumour proteome revealed differential abundance of proteins related to transcriptional regulation, RNA processing, protein translation, immune responses, and mitochondrial-associated metabolism. Correlation analysis identified associations between viral and human proteins, with several linked to biological processes previously implicated in DNA virus-host interactions. Further stratification of tumour by HHV-1 status showed consistent alterations in proteins associated with mitochondrial-associated metabolism, protein turnover, and cell adhesion/signalling.In summary, this study demonstrates the feasibility of metaproteomics for detecting viral components in archival GB tissues. Using this approach, we observed differences in viral protein landscape across cohorts and identified associations between viral presence and host proteomic features, providing a protein-level framework for future studies of virus-host interactions in GB.

Humans↗
PubMed2026

Genetic and molecular evidence linking CTSH to Alzheimer's disease pathophysiology.

INTRODUCTION: Lysosomal dysfunction contributes to Alzheimer's disease (AD) by impairing protein clearance and promoting neuroinflammation. Cathepsin H (CTSH), a lysosomal protease, recently emerged as a protective AD locus. We investigated how CTSH is regulated and how it influences early AD pathophysiology. METHODS: We analyzed genomic, transcriptomic, and proteomic data from cerebrospinal fluid (CSF) and brain tissue across three independent clinical and post mortem cohorts to assess CTSH regulation, expression, and disease associations. RESULTS: The coding variant rs2289702 acts as a cis-regulatory variant, altering CTSH mRNA and protein levels. The T allele associates with better cognition and reduced amyloid plaque burden. CSF CTSH correlates with total tau, phosphorylated tau181, neuronal markers, and multiple glial and complement-related inflammatory proteins. DISCUSSION: CTSH tracks early neurodegenerative, synaptic, and inflammatory changes, and co-expression analyses link it to broader immune-metabolic pathways. The findings position CTSH as a genetically regulated contributor to AD pathophysiology.

Humans↗
PubMed2005

Unchanged survival rates of 14-3-3gamma knockout mice after inoculation with pathological prion protein.

The diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) is based on typical clinical findings and is supported by a positive 14-3-3 Western blot of cerebrospinal fluid. However, it is not clear whether 14-3-3 indicates general neuronal damage or is of pathophysiological relevance in CJD. The fact that the 14-3-3 isoform spectrum in cerebrospinal fluid does not correspond to that found in the brain points to a regulated process. To investigate a possible role of 14-3-3 proteins in transmissible spongiform diseases, we generated a 14-3-3gamma-deficient mutant mouse line by using a classical knockout strategy. The anatomy and cage behavior of the mutant mice were normal. Western blot analyses of brain homogenates revealed no changes in the protein expression of other 14-3-3 isoforms (epsilon, beta, zeta, and eta). Proteomic analyses of mouse brains by two-dimensional differential gel electrophoresis showed that several proteins, including growth hormone, 1-Cys peroxiredoxin, CCT-zeta, glucose-6-phosphate isomerase, GRP170 precursor, and alpha-SNAP, were differentially expressed. Mutant and wild-type mice were inoculated either intracerebrally or intraperitoneally with the Rocky Mountain Laboratory strain of scrapie, but no differences were detected in the postinoculation survival rates. These results indicate that 14-3-3gamma is unlikely to play a causal role in CJD and related diseases.

14-3-3 Proteins↗
PubMedDate not supplied

Proteomic studies on low- and high-grade human brain astrocytomas.

Human brain astrocytomas range from the indolent low-grade to the highly infiltrating and aggressive high-grade form, also known as glioblastoma multiforme. The extensive heterogeneity of astrocytic tumors complicates their pathological classification. In this study, we compared the protein pattern of low-grade fibrillary astrocytomas to that of glioblastoma multiforme by 2D electrophoresis. The level of most proteins remains unchanged between the different grade tumors and only few differences are reproducibly observable. Fifteen differentially expressed proteins, as well as seventy conserved spots, were identified by mass spectrometry. Western and immnunohistochemical analysis confirmed the differential expression of the identified proteins. These data provide an initial reference map for brain gliomas. Among the proteins more highly expressed in glioblastoma multiforme, we found peroxiredoxin 1 and 6, the transcription factor BTF3, and alpha-B-crystallin, whereas protein disulfide isomerase A3, the catalytic subunit of the cAMP-dependent protein kinase, and the glial fibrillary acidic protein are increased in low-grade astrocytomas. Our findings contribute to deepening our knowledge of the factors that characterize this class of tumors and, at the same time, can be applied toward the development of novel molecular biomakers potentially useful for an accurate classification of the grade of astrocytomas.

Astrocytoma↗
PubMed2002

Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part II: dihydropyrimidinase-related protein 2, alpha-enolase and heat shock cognate 71.

Alzheimer's disease (AD) is a neurodegenerative disorder in which oxidative stress has been implicated as an important event in the progression of the pathology. In particular, it has been shown that protein modification by reactive oxygen species (ROS) occurs to a greater extent in AD than in control brain, suggesting a possible role for oxidation-related decrease in protein function in the process of neurodegeneration. Oxidative damage to proteins, assessed by measuring the protein carbonyl content, is involved in several events such as loss in specific protein function, abnormal protein clearance, depletion of the cellular redox-balance and interference with the cell cycle, and, ultimately, neuronal death. The present investigation represents a further step in understanding the relationship between oxidative modification of protein and neuronal death in AD. Previously, we used our proteomics approach, which successfully substitutes for labor-intensive immunochemical analysis, to detect proteins and identified creatine kinase, glutamine synthase and ubiquitin carboxy-terminal hydrolase L-1 as specifically oxidized proteins in AD brain. In this report we again applied our proteomics approach to identify new targets of protein oxidation in AD inferior parietal lobe (IPL). The dihydropyrimidinase related protein 2 (DRP-2), which is involved in the axonal growth and guidance, showed significantly increased level in protein carbonyls in AD brain, suggesting a role for impaired mechanism of neural network formation in AD. Additionally, the cytosolic enzyme alpha-enolase was identified as a target of protein oxidation and is involved the glycolytic pathway in the pathological events of AD. Finally, the heat shock cognate 71 (HSC-71) revealed increased, but not significant, oxidation in AD brain. These results are discussed with reference to potential involvement of these oxidatively modified proteins in neurodegeneration in AD brain.

Aged↗
PubMed2006

Liquid chromatography with tandem mass spectrometry-based proteomic discovery in aging and Alzheimer's disease.

Systems biology offers enormous potential to understand the complexity of human brain aging and neurodegenerative diseases. Proteomics has an important role in these investigations because of its unique strengths and because of the potential central pathogenic contribution of pathological protein to several of these diseases. Here we have reviewed the methods and presented some examples of liquid chromatography-electrospray ionization-tandem mass spectrometry-based proteomics, with and without quantification using isotope-coded affinity tags, in the investigation of aging and Alzheimer's disease. As protocols and methods for improved quantitative high-throughput proteomics constantly improve, this approach will likely continue to provide deeper insight into human brain aging and neurodegenerative diseases.

Aging↗
PubMedDate not supplied

Proteomics analyses of specific protein oxidation and protein expression in aged rat brain and its modulation by L-acetylcarnitine: insights into the mechanisms of action of this proposed therapeutic agent for CNS disorders associated with oxidative stress.

Impaired function of the central nervous system (CNS) in aged animals is associated with increased susceptibility to the development of many neurodegenerative diseases. Age-related functional deterioration in brain is consistent with the free radical theory of aging that predicts, among other things, that free radical reactions with and damage to biomolecules, such as proteins and membrane lipid bilayers, leads to loss of neurons and subsequently diminished cognition. These oxidatively modified biomolecules are believed to contribute to the decreased antioxidant content, mitochondrial dysfunction, and impaired plasticity in aged brains. Treatment of rodents with L-acetylcarnitine (LAC; gamma-trimethyl-beta-acetylbutyrobetaine) can improve these functional losses. Although it is well established that administration of LAC can decrease protein oxidation in aged brains, it is not clear which proteins are decreased in their level of oxidation in the brains of aged rats treated with LAC. The current study used a parallel redox proteomics approach to identify the proteins that are oxidized in aged rat cortex and hippocampus of aged rats. Moreover, those proteins that are reduced in oxidation status were identified in aged brains from rats treated in vivo with LAC. The findings are discussed in reference to brain aging and age-related cognitive impairment.

Acetylcarnitine↗
PubMed2006

Proteomics analysis of the actions of grape seed extract in rat brain: technological and biological implications for the study of the actions of psychoactive compounds.

Grape seed extract (GSE) is a commonly available dietary supplement taken for the anti-oxidant activity that's attributed to its proanthocyanidin (oligomers of monomeric polyphenols) content. Similar polyphenol-enriched preparations from blueberries and soy have shown protection against ovariectomy-induced or age-related cognitive deficits, suggesting that the molecular changes induced by these polyphenol preparations correlated with behavioral benefit. We hypothesized that ingestion of polyphenol-enriched preparations such as GSE would be manifested as protein changes that would be consistent with neuroprotection. Proteomics technology, namely 2D gel electrophoresis and mass spectrometry, identified quantitative changes in specific proteins induced in adult rat brain following ingestion of a powdered preparation of GSE. As recently reported [Deshane, J., Chaves, L., Sarikonda, K.V., Isbell, S., Wilson, L., Kirk, M., Grubbs, C., Barnes, S., Meleth, S. and Kim, H., 2004. Proteomics analysis of rat brain protein modulations by grape seed extract. Journal of Agricultural and Food Chemistry 52, 7872-7883.], the direction of change for the majority of the affected proteins was opposite to the direction the proteins were changed in either Alzheimer disease or in transgenic mouse models of dementia. A conservative conclusion is that GSE has neuroprotective activity, by affecting specific proteins in particular ways. In this chapter, elements of proteomics-type analysis are discussed that demonstrate the power of the technology to enable discovery of proteins involved in the response of the brain to a stimulus whether it be a dietary supplement, or a psychoactive drug. The fact that GSE affects proteins implicated in cognitive disorders suggests moreover that GSE may have impact on the actions of psychoactive drugs by maintaining an overall viability of the nervous system.

Animals↗
PubMed2000

Proteomics in molecular medicine: applications in central nervous systems disorders.

Bodily fluids such as cerebrospinal fluid (CSF) and serum can be analysed at the time of presentation and throughout the course of the disease. Changes in the protein composition of CSF may be indicative of altered CNS protein expression pattern with a causative or diagnostic disease link. These findings can be strengthened through subsequent proteomic analysis of specific brain areas implicated in the pathology. New isolation strategies of clinically relevant cellular material such as laser capture microdissection, protein enrichment procedures and proteomic approaches to neuropeptide and neurotransmitter analysis give us the opportunity to map out complex cellular interaction at an unprecedented level of detail. In neurological disorders multiple underlying pathogenic mechanisms as well as an acute and a chronic CNS disease components may require a selective repertoire of molecular targets and biomarkers rather than an individual protein to better define a complex disease. The resulting proteome database bypasses many ambiguities of experimental models and may facilitate pre- and clinical development of more specific disease markers and new selective fast acting therapeutics.

Animals↗
PubMed2006

140 mouse brain proteins identified by Ca2+-calmodulin affinity chromatography and tandem mass spectrometry.

Calmodulin is an essential Ca2+-binding protein that binds to a variety of targets that carry out critical signaling functions. We describe the proteomic characterization of mouse brain Ca2+-calmodulin-binding proteins that were purified using calmodulin affinity chromatography. Proteins in the eluates from four different affinity chromatography experiments were identified by 1-DE and in-gel digestion followed by LC-MS/MS. Parallel experiments were performed using two related control-proteins belonging to the EF-hand family. After comparing the results from the different experiments, we were able to exclude a significant number of proteins suspected to bind in a nonspecific manner. A total of 140 putative Ca2+-calmodulin-binding proteins were identified of which 87 proteins contained calmodulin-binding motifs. Among the 87 proteins that contained calmodulin-binding motifs, 48 proteins have not previously been shown to interact with calmodulin and 39 proteins were known calmodulin-binding proteins. Many proteins with ill-defined functions were identified as well as a number of proteins that at the time of the analysis were described only as ORFs. This study provides a functional framework for studies on these previously uncharacterized proteins.

Animals↗
PubMed2005

Comparative proteome analysis revealed up-regulation of transthyretin in rat brain under chronic clozapine treatment.

Long-term administration of antipsychotic drugs can induce differential expression of various proteins in brain cells, which may underscore the molecular mechanism of their clinical efficacy and/or side effects. We used two-dimensional gel electrophoresis in combination with mass spectrometry to screen differentially expressed proteins in the brain cells of rats under chronic clozapine treatment. We identified a protein, transthyretin, which was significantly up-regulated in the hippocampus of rats after four weeks' treatment of clozapine (20mg/kg) as compared with control animals. Western blot analysis further supported this finding. Besides, we also observed increased transcription of transthyretin mRNA in the cerebral cortex of rats under chronic treatment of clozapine (20mg/kg) or olanzapine (2mg/kg), but not haloperidol (1mg/kg), using real-time quantitative PCR. Transthyretin is a retinol carrier protein, our findings suggest that antipsychotic drugs treatment may affect the retinoid signaling cascade in the brain. Besides, transthyretin is also an indicator of nutritional status; increased transthyretin may be associated with the body weight gain of taking atypical antipsychotic drugs. This study also demonstrates that comparative proteome analysis is a feasible method to study the molecular mechanism of chronic antipsychotic drugs treatment.

Animals↗
PubMed2004

Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles.

Fragile X syndrome is caused by the absence of the fragile X mental retardation protein (FMRP). This RNA-binding protein is widely expressed in human and mouse tissues, and it is particularly abundant in the brain because of its high expression in neurons, where it localizes in the cell body and in granules throughout dendrites. Although FMRP is thought to regulate trafficking of repressed mRNA complexes and to influence local protein synthesis in synapses, it is not known whether it has additional functions in the control of translation in the cell body. Here, we have used recently developed approaches to investigate whether FMRP is associated with the translation apparatus. We demonstrate that, in the brain, FMRP is present in actively translating polyribosomes, and we show that this association is acutely sensitive to the type of detergent required to release polyribosomes from membranous structures. In addition, proteomic analyses of purified brain polyribosomes reveal the presence of several RNA-binding proteins that, similarly to FMRP, have been previously localized in neuronal granules. Our findings highlight the complex roles of FMRP both in actively translating polyribosomes and in repressed trafficking ribonucleoparticle granules.

Animals↗