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Results for “brain proteomics”

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PubMed2004

Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer's disease-linked mutations in amyloid precursor protein and presenilin 1.

The response of the hippocampal proteome to expression of mutant proteins present in familial forms of Alzheimer's disease (AD) was studied using transgenic rats. These animals carry both the amyloid precursor protein Swedish and 717 mutation (APP(SW+717)) as well as the presenilin 1 Finnish mutation (PS1(FINN)). This transgenic rat model displays intracellular amyloid beta (Abeta) in neurons of the neocortex and the hippocampus (CA2 and CA3). The hippocampus was selected as it is one of the first brain regions affected in AD and is involved in the processing of short-term memory and spatial memory. Applying a proteomic approach, we demonstrate that the expression of APP(SW+717) and PS1(FINN) transgenes causes changes in expression of hippocampal proteins, some of which have been previously linked to learning and memory formation. The protein alterations documented here occur in the absence of plaque formation and prior to the onset of cognitive deficits later observed in these transgenic rats. This indicates that molecular changes take place in the hippocampal neurons in response to expression of mutant proteins APP(SW+717) and PS1(FINN), which precede the occurrence of overt extracellular accumulation of extracellular amyloid. The implications of these findings on our understanding of the early stages of AD are discussed.

Alzheimer Disease↗

PubMed2026

Accurately Deciphering Tissue Heterogeneity From Spatial Multi-Modal and Multi-Omics With STransformer.

Advances in spatially resolved technologies enable the simultaneous acquisition of diverse data modalities within a tissue slice while preserving critical spatial context, which presents unprecedented opportunities to decipher intricate tissue heterogeneity. However, existing computational approaches lack the intrinsic flexibility to universally process both spatial multi-modal and multi-omics data. Here, we introduce STransformer, a unified deep learning framework designed to seamlessly accommodate a comprehensive landscape of spatial data. By simultaneously capturing short-range cellular interactions and tissue-wide semantic patterns, it extracts robust representations to accurately dissect complex tissue heterogeneity. Systematic evaluations across diverse species, tissue types, and data modalities highlight its profound versatility. For spatial multi-modal data, STransformer delineates intricate anatomical structures in the human cortex, uncovers pathological mechanisms in Alzheimer's disease, and characterizes dynamic spatiotemporal developmental trajectories during chicken cardiogenesis. Scaling to spatial multi-omics data, STransformer synergizes spatial transcriptomic and proteomic profiles to decipher intricate immune microenvironments within the human tonsil, and jointly analyzes spatial epigenomic and transcriptomic data to infer regulatory mechanisms in the mouse embryonic brain. Consequently, STransformer serves as a highly versatile and robust analytical framework for advancing our understanding of tissue heterogeneity and disease pathogenesis.

Multiomics↗

PubMed2003

Proteomic characterization of the human cortical neuronal cell line HCN-2.

Neuronal marker proteins are widely used for characterization and identification of normal and tumor tissue of the central nervous system, but the most commonly used neuronal markers have inherent methodological problems. We used a proteomic approach with two-dimensional (2-D) gel electrophoresis and subsequent MALDI identification to identify possible new marker proteins in the human cortical neuronal cell line HCN-2. We found 14 proteins that previously were predicted only on the basis of open reading frames from mRNA sequences or DNA. We could unambiguously identify the following proteins: Bab55091, BK65A6.2 (Novel Sushi Domain (Scr repeat), glucosidase II alpha subunit, glucosidase II precursor (KIAA0088 protein), HSPC108, hypothetical 35.8 kDa protein, hypothetical 40.7 KDA protein, hypothetical 49.4 kDa protein, leucine-zipper protein FKSG13, lysophospholipase homolog, mitofilin (fragment), P1.11659_4, reticulocabin precursor and one unknown protein for MGC:10432. We could prove the existence of these 14 proteins in the human neuron, extending the list of proteins with neuronal expression and identify possible new candidate marker proteins.

Biomarkers↗

PubMed2006

The dopamine transporter proteome.

Dopamine (DA) uptake through the neuronal plasma membrane DA transporter (DAT) is essential for the maintenance of normal DA homeostasis in the brain. The DAT-mediated re-uptake system limits not only the intensity but also the duration of DA actions at presynaptic and postsynaptic receptors. This protein is the primary target for cocaine and amphetamine, both highly addictive and major substances of abuse worldwide. DAT is also the molecular target for therapeutic agents used in the treatment of mental disorders, such as attention deficit hyperactivity disorder and depression. Given the role played by the DAT in regulation of DA neurotransmission and its contribution to the abuse potential of psychostimulants, it becomes not only important but also necessary to understand the functional regulation of this protein. To investigate the cellular and molecular mechanisms associated with DAT function and regulation, our laboratory and others have embarked on a systematic search for DAT protein-protein interactions. Recently, a growing number of proteins have been shown to interact with DAT. These novel interactions might be important in the assembly, targeting, trafficking and/or regulation of transporter function. In this review, I summarize the main findings obtained from the characterization of DAT-interacting proteins and discuss the functional implications of these novel interactions. Based on these new data, I propose to use the term DAT proteome to explain how interacting proteins regulate DAT function. These novel interactions might help define new mechanisms associated with the function of the transporter.

Animals↗

PubMed2001

Cell encapsulation technology as a therapeutic strategy for CNS malignancies.

Gene therapy using viral vectors has to date failed to reveal its definitive clinical usefulness. Cell encapsulation technology represents an alternative, nonviral approach for the delivery of biologically active compounds to tumors. This strategy involves the use of genetically engineered producer cells that secrete a protein with therapeutic potential. The cells are encapsulated in an immunoisolating material that makes them suitable for transplantation. The capsules, or bioreactors, permit the release of recombinant proteins that may assert their effects in the tumor microenvironment. During the last decades, there has been significant progress in the development of encapsulation technologies that comprise devices for both macro- and microencapsulation. The polysaccharide alginate is the most commonly used material for cell encapsulation and is well tolerated by various tissues. A wide spectrum of cells and tissues has been encapsulated and implanted, both in animals and humans, indicating the general applicability of this approach for both research and medical purposes, including CNS malignancies. Gliomas most frequently recur at the resection site. To provide local and sustained drug delivery, the bioreactors can be implanted in the brain parenchyma or in the ventricular system. The development of comprehensive analyses of geno- and phenotypic profiles of a tumor (genomics and proteomics) may provide new and important guidelines for choosing the optimal combination of bioreactors and recombinant proteins for therapeutic use.

Alginates↗

PubMed2004

Proteomic analysis of native metabotropic glutamate receptor 5 protein complexes reveals novel molecular constituents.

We used a proteomic approach to identify novel proteins that may regulate metabotropic glutamate receptor 5 (mGluR5) responses by direct or indirect protein interactions. This approach does not rely on the heterologous expression of proteins and offers the advantage of identifying protein interactions in a native environment. The mGluR5 protein was immunoprecipitated from rat brain lysates; co-immunoprecipitating proteins were analyzed by mass spectrometry and identified peptides were matched to protein databases to determine the correlating parent proteins. This proteomic approach revealed the interaction of mGluR5 with known regulatory proteins, as well as novel proteins that reflect previously unidentified molecular constituents of the mGluR5-signaling complex. Immunoblot analysis confirmed the interaction of high confidence proteins, such as phosphofurin acidic cluster sorting protein 1, microtubule-associated protein 2a and dynamin 1, as mGluR5-interacting proteins. These studies show that a proteomic approach can be used to identify candidate interacting proteins. This approach may be particularly useful for neurobiology applications where distinct protein interactions within a signaling complex can dramatically alter the outcome of the response to neurotransmitter release, or the disruption of normal protein interactions can lead to severe neurological and psychiatric disorders.

Algorithms↗

PubMed2022

Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease.

Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation. Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.

Humans↗

PubMed2006

The fatty-acid amide hydrolase inhibitor URB597 does not affect triacylglycerol hydrolysis in rat tissues.

The O-arylcarbamate URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester; also referred to as KDS-4103) is a potent inhibitor of fatty-acid amide hydrolase (FAAH), an intracellular serine hydrolase responsible for the inactivation of the endogenous cannabinoid anandamide. URB597 demonstrates a remarkable degree of selectivity for FAAH over other serine hydrolases (e.g. cholinesterases) or other components of the endocannabinoid system (e.g. cannabinoid receptors). However, in a proteomic-based selectivity screen based on the displacement of fluorophosphonate-rhodamine (FPR) from mouse brain proteins, it was recently shown that URB597 prevents FPR binding to triacylglycerol hydrolase (TGH) with a median inhibitory concentration of 192nM. To determine whether this effect correlates with inhibition of TGH activity, we investigated the ability of URB597 to inhibit triolein hydrolysis in rat liver and heart tissues, which are rich in TGH, as well as white adipose tissue (WAT), which is rich in adipose triacylglycerol lipase (TGL) and hormone-sensitive lipase. The results show that URB597 does not affect triolein hydrolysis in any of these tissues at concentrations as high as 10microM, whereas it inhibits FAAH activity at low nanomolar concentrations. Moreover, intraperitoneal (i.p.) administration of URB597 at doses that maximally inhibit FAAH in vivo (0.3-3mgkg(-1)) exerts no effect on triolein hydrolysis and tissue triacylglycerol (TAG) levels in rat liver, heart or WAT. The results indicate that URB597, while potent at inhibiting FAAH, does not affect TGH and TGL activities in rat tissues.

Adipose Tissue, White↗

PubMed2000

Proteomic analysis of NMDA receptor-adhesion protein signaling complexes.

N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.

Animals↗

PubMed2004

Treatment and control of human African trypanosomiasis.

PURPOSE OF REVIEW: Access to treatment is a multi-step process and little progress has been made to improve treatments for sleeping sickness over the past 50 years. The current strategy is based on diagnostic tools developed in the 1960s while available drugs are still the same as those developed in the middle of the last century. Strategic opportunities can only be based on two achievements: improved diagnosis and safer drugs. This paper reviews the development of new diagnostic tools and drugs and the opportunity offered by new technologies for their further improvement. RECENT FINDINGS: The prodrug DB289 shows excellent oral activity with low toxicity for the treatment of early-stage sleeping sickness; it has recently entered phase II(b) clinical trials. The recent ability to identify and test specific host and parasite biomarkers has allowed the development of new, more-specific and sensitive, diagnostic and stage-determination tools. The accurate diagnosis of an infection by use of proteomic signature analysis has been achieved. Urinary nitrites and nitrates follow closely the increase of brain nitric oxide associated with the penetration of trypanosomes in the brain. Sleep-onset rapid eye movement-like episodes have been shown to occur at onset of late-stage trypanosomiasis. This unique disturbance of the wake/sleep cycle seems to be the first pathognomonic sign in the occurrence of late-stage trypanosomiasis. SUMMARY: Following the description of the disease, and diagnostic tools and drugs that have been used, and are still in use today, the authors show how it has influenced over time the evolution of strategies for surveillance and control. Recent developments and prospects for new, more-specific and sensitive diagnostic tools and a safer drug will undoubtedly improve the accuracy of patient recruitment and facilitate treatment, and provide ways towards new strategic opportunities.

Animals↗

PubMed2005

Biomarkers in psychotropic drug development: integration of data across multiple domains.

This review focuses on the current status of biomarkers and/or approaches critical to assessing novel neuroscience targets with an emphasis on new paradigms and challenges in this field of research. The importance of biomarker data integration for psychotropic drug development is illustrated with examples for clinically used medications and investigational drugs. The question remains how to verify access to the brain. Early imaging studies including micro-PET can help to overcome this. However, in case of delayed tracer development or because of no feasible application of brain imaging effects of the molecule, using CSF as a matrix could fill this gap. Proteomic research using CSF will hopefully have a major impact on the development of treatments for psychiatric disorders.

Animals↗

PubMed2005

The role of proteomics in investigating psychiatric disorders.

Proteomics is the study of protein expression and function on a genome-wide scale and its application in psychiatric research is relatively new. As protein expression is the mediator of genetic vulnerabilities, it is critical that this area is explored further to increase our understanding of psychiatric disease and reveal potential new treatments.

Brain↗

PubMed2001

Psychogenomics: opportunities for understanding addiction.

The term psychogenomics is used here to describe the process of applying the powerful tools of genomics and proteomics to achieve a better understanding of the biological substrates of normal behavior and of diseases of the brain that manifest themselves as behavioral abnormalities. Applying psychogenomics to the study of drug addiction will lead to the identification of genes and their protein products that control the reward pathways of the brain and their adaptations to drugs of abuse, as well as variations in these genes that confer genetic risk for addiction and related disorders. The ultimate goal is to use this information to develop more effective treatments for these disorders as well as objective diagnostic tools, preventive measures, and eventually cures.

Animals↗

PubMed2005

Amyotrophic lateral sclerosis: new developments in diagnostic markers.

There is an intensive search for diagnostic markers in amyotrophic lateral sclerosis (ALS). Protein analysis (proteomics) of the cerebrospinal fluid (CSF) appears particularly promising using mass spectrometry and 2-D gel electrophoresis to detect low and high molecular weight proteins, respectively. It is open whether protein changes specific for ALS will be found. This also holds true for inflammatory proteins such as the cytokine monocyte chemoattractant protein-1 which has been detected in CSF in ALS and for other cytokines such as interleukin-1beta. Increases of the protein Nogo A and B in muscle tissue and decreases of the growth factor vascular endothelial growth factor in blood may also be useful for monitoring the course of ALS. Clinical neurophysiology provides markers for upper and lower motor neuron damage. A very sensitive method to detect early upper motor neuron involvement is the transcranial magnetic stimulation modification 'triple stimulation technique' which can show significant changes in patients without clinical upper motor neuron signs. The loss of lower motor neurons can be closely monitored by MUNE techniques (motor unit number estimate). In modern imaging, the MRI technique DTI (diffusion tensor imaging) has the greatest diagnostic potential for ALS. It can separate between normal and ALS in group comparisons and may be improved to be diagnostic in individual patients. Voxel-based morphometry can reliably demonstrate regional cortical atrophy in motor areas and beyond although it is not appropriate for use in individual patients.

Amyotrophic Lateral Sclerosis↗

PubMed2001

From cDNA microarrays to high-throughput proteomics. Implications in the search for preventive initiatives to slow the clinical progression of Alzheimer's disease dementia.

Alzheimer's disease (AD) is the most common form of dementia, affecting as many as four million elderly people. lt results from abnormal changes in the brain that most likely begin long before cognitive impairment and other clinical symptoms become apparent. Little is known about the changes preceding or accompanying initiation of the disease. Using cDNA microarray, we previously reported candidate gene products whose expression is altered in the cerebral cortex of cases at risk for AD dementia. However, it is possible that the cDNA microarray evidence might have underestimated post-transcriptional modifications, and as a result, provided only a partial view of the biological problem of interest. Based on this hypothesis, we initiated a series of parallel high-throughput proteomic studies. We found that, consistent with the cDNA microarray evidence, the expression of proteins involved in synaptic activities was also altered in the brains of early AD cases. These studies support the feasibility and usefulness of high-throughput cDNA and protein microarray techniques to examine the sequential changes of distinctive gene expression patterns in the brain as a function of the progression of AD dementia. Our preliminary results also support the utility of high-throughput proteomic methodologies as a means to identify novel AD biomarkers from cerebral spinal fluid and/or from serum.

Alzheimer Disease↗

PubMed2004

A calmodulin-regulated protein kinase linked to neuron survival is a substrate for the calmodulin-regulated death-associated protein kinase.

Death-associated protein kinase (DAPK) is a calmodulin (CaM)-regulated protein kinase and a drug-discovery target for neurodegenerative diseases. However, a protein substrate relevant to neuronal death had not been described. We identified human brain CaM-regulated protein kinase kinase (CaMKK), an enzyme key to neuronal survival, as the first relevant substrate protein by using a focused proteomics- and informatics-based approach that can be generalized to protein kinase open reading frames identified in genome projects without prior knowledge of biochemical context. First, DAPK-interacting proteins were detected in yeast two-hybrid screens and in immunoprecipitates of brain extracts. Second, potential phosphorylation site sequences in yeast two-hybrid hits were identified on the basis of our previous results from positional-scanning synthetic-peptide substrate libraries and molecular modeling. Third, reconstitution assays using purified components demonstrated that DAPK phosphorylates CaMKK with a stoichiometry of nearly 1 mol of phosphate per mole of CaMKK and a K(m) value of 3 microM. Fourth, S511 was identified as the phosphorylation site by peptide mapping using mass spectrometry, site-directed mutagenesis, and Western blot analysis with a site-directed antisera targeting the phosphorylated sequence. Fifth, a potential mechanism of action was identified on the basis of the location of S511 near the CaM recognition domain of CaMKK and demonstrated by attenuation of CaM-stimulated CaMKK autophosphorylation after DAPK phosphorylation. The results raise the possibility of a CaM-regulated protein kinase cascade as a key mechanism in acute neurodegeneration amenable to therapeutic targeting.

Amino Acid Sequence↗

PubMed2003

Genomic and proteomic analysis of multiple sclerosis. Opinion.

Multiple sclerosis (MS) and other autoimmune diseases result from the dysregulation of genetic and proteomic programs. In MS, the loss of immune homeostasis leads to aberrant targeting and destruction of the myelin sheath, which manifests as the clinical syndrome of MS. The advent of technologies to perform large-scale analysis of mRNA transcript and protein expression will transform our understanding of the mechanisms underlying the initiation and progression of MS, and will yield new targets for therapeutic intervention.

Animals↗

PubMed2004

High-resolution proteomic mapping in the vertebrate central nervous system: close proximity of connexin35 to NMDA glutamate receptor clusters and co-localization of connexin36 with immunoreactivity for zonula occludens protein-1 (ZO-1).

Combined confocal microscopy and freeze-fracture replica immunogold labeling (FRIL) were used to examine the connexin identity at electrical synapses in goldfish brain and rat retina, and to test for "co-localization" vs. "close proximity" of connexins to other functionally interacting proteins in synapses of goldfish and mouse brain and rat retina. In goldfish brain, confocal microscopy revealed immunofluorescence for connexin35 (Cx35) and NMDA-R1 (NR1) glutamate receptor protein in Mauthner Cell/Club Ending synapses. By FRIL double labeling, NR1 glutamate receptors were found in clusters of intramembrane particles in the postsynaptic membrane extraplasmic leaflets, and these distinctive postsynaptic densities were in close proximity (0.1-0.3 microm) to neuronal gap junctions labeled for Cx35, which is the fish ortholog of connexin36 (Cx36) found at neuronal gap junctions in mammals. Immunogold labeling for Cx36 in adult rat retina revealed abundant gap junctions, including several previously unrecognized morphological types. As in goldfish hindbrain, immunogold double labeling revealed NR1-containing postsynaptic densities localized near Cx36-labeled gap junction in rat inferior olive. Confocal immunofluorescence microscopy revealed widespread co-localization of Cx36 and ZO-1, particularly in the reticular thalamic nucleus and amygdala of mouse brain. By FRIL, ZO-1 immunoreactivity was co-localized with Cx36 at individual gap junction plaques in rat retinal neurons. As cytoplasmic accessory proteins, ZO-1 and possibly related members of the membrane-associated guanylate kinase (MAGUK) family represent scaffolding proteins that may bind to and regulate the activity of many neuronal gap junctions. These data document the power of combining immunofluorescence confocal microscopy with FRIL ultrastructural imaging and immunogold labeling to determine the relative proximities of proteins that are involved in short- vs. intermediate-range molecular interactions in the complex membrane appositions at synapses between neurons.

Animals↗