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Neuroproteomics
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Neuroproteomics

A special issue of Proteomes (ISSN 2227-7382).

Deadline for manuscript submissions: closed (15 March 2019) | Viewed by 117633

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Angus C. Nairn

E-Mail Website
Guest Editor
1. Charles B. G. Murphy Professor of Psychiatry, Co-Director, Yale/NIDA Neuroproteomics Center, New Haven, CT, USA
2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
Interests: dopamine; Alzheimer disease; Parkinson disease; protein phosphorylation; signal transduction
Special Issues, Collections and Topics in MDPI journals
Dr. Kenneth R. Williams

E-Mail Website
Guest Editor
1. Professor (Adjunct) of Research, Co-Director, Yale/NIDA Neuroproteomics Center, New Haven, CT, USA
2. Founder, Keck Foundation Biotechnology Resource Laboratory, Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, CT, USA
Interests: mass spectrometry; quantitative proteomics; neuroproteomics; disease biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advances in mass spectrometry (MS) instrumentation that enable the level of quantitation of expression of ~8000 proteins to be interrogated by LC/MS/MS analysis have opened the door to the proteome and already are having an impact that extends from biology to clinical proteomics. With no theoretical limits in sight with regard to further improvements in MS instrumentation and when coupled with new chemical labelling technologies that incorporate multiple isobaric tags that enable the concurrent analyses of up to 11 different samples using commercially available reagents, and improved peptide identification algorithms and bioinformatics; the future of MS-based, quantitative proteomics is incredibly promising and exciting for mass spectrometrists and for the much larger numbers of investigators whose research now depends upon MS/proteomics analyses. While these methods are beginning to be applied to neuroproteomics, the central nervous system (CNS) poses many challenges to quantitative proteomics that begin with the immense level of cellular and sub-cellular heterogeneity. The CNS has ~100 billion neurons, each with 10,000 to 100,000 synaptic connections; and even larger numbers of glial cells. Moreover, there is a large variety in cell morphology with individual neurons typically being intermingled in close contact with several different types of neurons and with axonal projections from an individual neuron often projecting over relatively long distances. Given that it is now clear that each of the ~1000 individual types of nerve cells exhibit distinct patterns of gene expression, it is critically important to develop and publish the technologies and methodologies needed to enable quantitative MS/proteomic analyses of specific neuronal cell types and their organelles.

While the whole brain or large regions of brain tissue can be used for proteomic analysis, the useful information that can be gathered is limited because of cellular and sub-cellular heterogeneity. Analysis of mixed populations of distinct cell types not only limits our understanding of where a particular protein expression change might have occurred, it also minimizes our ability to detect significant changes in protein expression and/or modification levels due to issues related to low signal to high noise.

This Special Issue will contain research and review articles that cover whole proteome analysis, comparative proteomics, protein structure/function, protein post-translational modifications, protein:ligand and protein:protein interactions within normal and diseased neurological tissues. Since the huge level of cellular and sub-cellular heterogeneity in the CNS is the greatest obstacle impeding progress towards understanding the adaptive molecular changes that underlie drug addiction and that occur in other neurological diseases, we are especially interested in manuscripts that describe the use of laser capture microscopy, fluorescence cytometry-related, and immuno-affinity technologies in conjunction with transgenic and viral methods to isolate and study neural cell type- and organelle-specific proteomes. Manuscripts are also especially sought that describe the development and use of technologies such as “Top-Down” to identify combinatorial epigenetic changes in histone modification and targeted MS to obviate the stochastic nature of discovery MS/proteomics that are applicable to neurological analyses. Another area of special interest is the use of bioinformatics approaches to integrate RNA and protein level analyses so peptide identification rates can be improved by carrying out MS/MS database searches on brain region- and cell type-specific proteomes that have been predicted based on RNA-sequencing.

We very much look forward to receiving your manuscripts and compiling an outstanding collection of review and original research articles that will advance the field of neuroproteomics.

Sincerely,

Prof. Dr. Angus C. Nairn
Dr. Kenneth R. Williams
Guest Editors

Manuscript Submission Information

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Keywords

  • neuroproteomics
  • quantitative proteomics
  • isobaric chemical labeling
  • label-free quantitation
  • parallel reaction monitoring
  • multiple reaction monitoring
  • mass spectrometry
  • discovery mass spectrometry
  • targeted mass spectrometry
  • data-dependent acquisition
  • data-independent acquisition

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Published Papers (18 papers)

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Editorial

Jump to: Research, Review, Other

9 pages, 197 KiB  
Editorial
Editorial for Special Issue: Neuroproteomics
by Kenneth R. Williams and Angus C. Nairn
Proteomes 2019, 7(2), 24; https://doi.org/10.3390/proteomes7020024 - 31 May 2019
Cited by 1 | Viewed by 4089
Abstract
Recent advances in mass spectrometry (MS) instrumentation [...] Full article
(This article belongs to the Special Issue Neuroproteomics)

Research

Jump to: Editorial, Review, Other

22 pages, 3348 KiB  
Article
Development of Targeted Mass Spectrometry-Based Approaches for Quantitation of Proteins Enriched in the Postsynaptic Density (PSD)
by Rashaun S. Wilson, Navin Rauniyar, Fumika Sakaue, TuKiet T. Lam, Kenneth R. Williams and Angus C. Nairn
Proteomes 2019, 7(2), 12; https://doi.org/10.3390/proteomes7020012 - 2 Apr 2019
Cited by 16 | Viewed by 7828
Abstract
The postsynaptic density (PSD) is a structural, electron-dense region of excitatory glutamatergic synapses, which is involved in a variety of cellular and signaling processes in neurons. The PSD is comprised of a large network of proteins, many of which have been implicated in [...] Read more.
The postsynaptic density (PSD) is a structural, electron-dense region of excitatory glutamatergic synapses, which is involved in a variety of cellular and signaling processes in neurons. The PSD is comprised of a large network of proteins, many of which have been implicated in a wide variety of neuropsychiatric disorders. Biochemical fractionation combined with mass spectrometry analyses have enabled an in-depth understanding of the protein composition of the PSD. However, the PSD composition may change rapidly in response to stimuli, and robust and reproducible methods to thoroughly quantify changes in protein abundance are warranted. Here, we report on the development of two types of targeted mass spectrometry-based assays for quantitation of PSD-enriched proteins. In total, we quantified 50 PSD proteins in a targeted, parallel reaction monitoring (PRM) assay using heavy-labeled, synthetic internal peptide standards and identified and quantified over 2100 proteins through a pre-determined spectral library using a data-independent acquisition (DIA) approach in PSD fractions isolated from mouse cortical brain tissue. Full article
(This article belongs to the Special Issue Neuroproteomics)
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17 pages, 12351 KiB  
Article
Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels
by Mark L. Sowers, Jessica Di Re, Paul A. Wadsworth, Alexander S. Shavkunov, Cheryl Lichti, Kangling Zhang and Fernanda Laezza
Proteomes 2019, 7(1), 5; https://doi.org/10.3390/proteomes7010005 - 23 Jan 2019
Cited by 11 | Viewed by 5518
Abstract
Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14−/− mice recapitulate the salient endophenotypes of synaptic dysfunction and [...] Read more.
Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14−/− mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14−/− model may provide a valuable tool to interrogate pathways related to disease mechanisms. Here, we performed label-free quantitative proteomics to identify enriched pathways in both male and female hippocampi from Fgf14+/+ and Fgf14−/− mice. We discovered that all of the differentially expressed proteins measured in Fgf14−/− animals, relative to their same-sex wildtype counterparts, are associated with SZ based on genome-wide association data. In addition, measured changes in the proteome were predominantly sex-specific, with the male Fgf14−/− mice distinctly enriched for pathways associated with neuropsychiatric disorders. In the male Fgf14−/− mouse, we found molecular characteristics that, in part, may explain a previously described neurotransmission and behavioral phenotype. This includes decreased levels of ALDH1A1 and protein kinase A (PRKAR2B). ALDH1A1 has been shown to mediate an alternative pathway for gamma-aminobutyric acid (GABA) synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the Fgf14−/− mouse as a useful preclinical model of SZ for generating hypotheses on disease mechanisms, sex-specific manifestation, and therapy. Full article
(This article belongs to the Special Issue Neuroproteomics)
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22 pages, 2686 KiB  
Article
Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization
by Darryl S. Watkins, Jason D. True, Amber L. Mosley and Anthony J. Baucum II
Proteomes 2018, 6(4), 53; https://doi.org/10.3390/proteomes6040053 - 17 Dec 2018
Cited by 10 | Viewed by 4648 | Correction
Abstract
Glutamatergic projections from the cortex and dopaminergic projections from the substantia nigra or ventral tegmental area synapse on dendritic spines of specific GABAergic medium spiny neurons (MSNs) in the striatum. Direct pathway MSNs (dMSNs) are positively coupled to protein kinase A (PKA) signaling [...] Read more.
Glutamatergic projections from the cortex and dopaminergic projections from the substantia nigra or ventral tegmental area synapse on dendritic spines of specific GABAergic medium spiny neurons (MSNs) in the striatum. Direct pathway MSNs (dMSNs) are positively coupled to protein kinase A (PKA) signaling and activation of these neurons enhance specific motor programs whereas indirect pathway MSNs (iMSNs) are negatively coupled to PKA and inhibit competing motor programs. An imbalance in the activity of these two programs is observed following increased dopamine signaling associated with exposure to psychostimulant drugs of abuse. Alterations in MSN signaling are mediated by changes in MSN protein post-translational modifications, including phosphorylation. Whereas direct changes in specific kinases, such as PKA, regulate different effects observed in the two MSN populations, alterations in the specific activity of serine/threonine phosphatases, such as protein phosphatase 1 (PP1) are less well known. This lack of knowledge is due, in part, to unknown, cell-specific changes in PP1 targeting proteins. Spinophilin is the major PP1-targeting protein in striatal postsynaptic densities. Using proteomics and immunoblotting approaches along with a novel transgenic mouse expressing hemagglutainin (HA)-tagged spinophilin in dMSNs and iMSNs, we have uncovered cell-specific regulation of the spinophilin interactome following a sensitizing regimen of amphetamine. These data suggest regulation of spinophilin interactions in specific MSN cell types and may give novel insight into putative cell-specific, phosphatase-dependent signaling pathways associated with psychostimulants. Full article
(This article belongs to the Special Issue Neuroproteomics)
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27 pages, 3722 KiB  
Article
Mapping the Proteome of the Synaptic Cleft through Proximity Labeling Reveals New Cleft Proteins
by Tony Cijsouw, Austin M. Ramsey, TuKiet T. Lam, Beatrice E. Carbone, Thomas A. Blanpied and Thomas Biederer
Proteomes 2018, 6(4), 48; https://doi.org/10.3390/proteomes6040048 - 28 Nov 2018
Cited by 41 | Viewed by 12215
Abstract
Synapses are specialized neuronal cell-cell contacts that underlie network communication in the mammalian brain. Across neuronal populations and circuits, a diverse set of synapses is utilized, and they differ in their molecular composition to enable heterogenous connectivity patterns and functions. In addition to [...] Read more.
Synapses are specialized neuronal cell-cell contacts that underlie network communication in the mammalian brain. Across neuronal populations and circuits, a diverse set of synapses is utilized, and they differ in their molecular composition to enable heterogenous connectivity patterns and functions. In addition to pre- and post-synaptic specializations, the synaptic cleft is now understood to be an integral compartment of synapses that contributes to their structural and functional organization. Aiming to map the cleft proteome, this study applied a peroxidase-mediated proximity labeling approach and used the excitatory synaptic cell adhesion protein SynCAM 1 fused to horseradish peroxidase (HRP) as a reporter in cultured cortical neurons. This reporter marked excitatory synapses as measured by confocal microcopy and was targeted to the edge zone of the synaptic cleft as determined using 3D dSTORM super-resolution imaging. Proximity labeling with a membrane-impermeant biotin-phenol compound restricted labeling to the cell surface, and Label-Free Quantitation (LFQ) mass spectrometry combined with ratiometric HRP tagging of membrane vs. synaptic surface proteins was used to identify the proteomic content of excitatory clefts. Novel cleft candidates were identified, and Receptor-type tyrosine-protein phosphatase zeta was selected and successfully validated. This study supports the robust applicability of peroxidase-mediated proximity labeling for synaptic cleft proteomics and its potential for understanding synapse heterogeneity in health and changes in diseases such as psychiatric disorders and addiction. Full article
(This article belongs to the Special Issue Neuroproteomics)
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Graphical abstract

16 pages, 2572 KiB  
Article
Evaluation of the Phosphoproteome of Mouse Alpha 4/Beta 2-Containing Nicotinic Acetylcholine Receptors In Vitro and In Vivo
by Megan B. Miller, Rashaun S. Wilson, TuKiet T. Lam, Angus C. Nairn and Marina R. Picciotto
Proteomes 2018, 6(4), 42; https://doi.org/10.3390/proteomes6040042 - 15 Oct 2018
Cited by 11 | Viewed by 5108
Abstract
Activation of nicotinic acetylcholine receptors containing α4 and β2 subunits (α4/β2* nAChRs) in the mammalian brain is necessary for nicotine reinforcement and addiction. We previously identified interactions between α4/β2* nAChRs and calcium/calmodulin-dependent protein kinase II (CaMKII) in mouse and human brain tissue. Following [...] Read more.
Activation of nicotinic acetylcholine receptors containing α4 and β2 subunits (α4/β2* nAChRs) in the mammalian brain is necessary for nicotine reinforcement and addiction. We previously identified interactions between α4/β2* nAChRs and calcium/calmodulin-dependent protein kinase II (CaMKII) in mouse and human brain tissue. Following co-expression of α4/β2 nAChR subunits with CaMKII in HEK cells, mass spectrometry identified 8 phosphorylation sites in the α4 subunit. One of these sites and an additional site were identified when isolated α4/β2* nAChRs were dephosphorylated and subsequently incubated with CaMKII in vitro, while 3 phosphorylation sites were identified following incubation with protein kinase A (PKA) in vitro. We then isolated native α4/β2* nAChRs from mouse brain following acute or chronic exposure to nicotine. Two CaMKII sites identified in HEK cells were phosphorylated, and 1 PKA site was dephosphorylated following acute nicotine administration in vivo, whereas phosphorylation of the PKA site was increased back to baseline levels following repeated nicotine exposure. Significant changes in β2 nAChR subunit phosphorylation were not observed under these conditions, but 2 novel sites were identified on this subunit, 1 in HEK cells and 1 in vitro. These experiments identified putative CaMKII and PKA sites on α4/β2* nAChRs and novel nicotine-induced phosphorylation sites in mouse brain that can be explored for their consequences on receptor function. Full article
(This article belongs to the Special Issue Neuroproteomics)
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19 pages, 3473 KiB  
Article
Phosphoproteomic Analysis of the Amygdala Response to Adolescent Glucocorticoid Exposure Reveals G-Protein Coupled Receptor Kinase 2 as a Target for Reducing Motivation for Alcohol
by Megan L. Bertholomey, Kathryn Stone, TuKiet T. Lam, Seojin Bang, Wei Wu, Angus C. Nairn, Jane R. Taylor and Mary M. Torregrossa
Proteomes 2018, 6(4), 41; https://doi.org/10.3390/proteomes6040041 - 12 Oct 2018
Cited by 4 | Viewed by 4553
Abstract
Early life stress is associated with risk for developing alcohol use disorders (AUDs) in adulthood. Though the neurobiological mechanisms underlying this vulnerability are not well understood, evidence suggests that aberrant glucocorticoid and noradrenergic system functioning play a role. The present study investigated the [...] Read more.
Early life stress is associated with risk for developing alcohol use disorders (AUDs) in adulthood. Though the neurobiological mechanisms underlying this vulnerability are not well understood, evidence suggests that aberrant glucocorticoid and noradrenergic system functioning play a role. The present study investigated the long-term consequences of chronic exposure to elevated glucocorticoids during adolescence on the risk of increased alcohol-motivated behavior, and on amygdalar function in adulthood. A discovery-based analysis of the amygdalar phosphoproteome using mass spectrometry was employed, to identify changes in function. Adolescent corticosterone (CORT) exposure increased alcohol, but not sucrose, self-administration, and enhanced stress-induced reinstatement with yohimbine in adulthood. Phosphoproteomic analysis indicated that the amygdala phosphoproteome was significantly altered by adolescent CORT exposure, generating a list of potential novel mechanisms involved in the risk of alcohol drinking. In particular, increased phosphorylation at serines 296–299 on the α2A adrenergic receptor (α2AAR), mediated by the G-protein coupled receptor kinase 2 (GRK2), was evident after adolescent CORT exposure. We found that intra-amygdala infusion of a peptidergic GRK2 inhibitor reduced alcohol seeking, as measured by progressive ratio and stress reinstatement tests, and induced by the α2AAR antagonist yohimbine. These results suggest that GRK2 represents a novel target for treating stress-induced motivation for alcohol which may counteract alterations in brain function induced by adolescent stress exposure. Full article
(This article belongs to the Special Issue Neuroproteomics)
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20 pages, 4826 KiB  
Article
Proteases Shape the Chlamydomonas Secretome: Comparison to Classical Neuropeptide Processing Machinery
by Raj Luxmi, Crysten Blaby-Haas, Dhivya Kumar, Navin Rauniyar, Stephen M. King, Richard E. Mains and Betty A. Eipper
Proteomes 2018, 6(4), 36; https://doi.org/10.3390/proteomes6040036 - 23 Sep 2018
Cited by 24 | Viewed by 5719
Abstract
The recent identification of catalytically active peptidylglycine α-amidating monooxygenase (PAM) in Chlamydomonas reinhardtii, a unicellular green alga, suggested the presence of a PAM-like gene and peptidergic signaling in the last eukaryotic common ancestor (LECA). We identified prototypical neuropeptide precursors and essential peptide [...] Read more.
The recent identification of catalytically active peptidylglycine α-amidating monooxygenase (PAM) in Chlamydomonas reinhardtii, a unicellular green alga, suggested the presence of a PAM-like gene and peptidergic signaling in the last eukaryotic common ancestor (LECA). We identified prototypical neuropeptide precursors and essential peptide processing enzymes (subtilisin-like prohormone convertases and carboxypeptidase B-like enzymes) in the C. reinhardtii genome. Reasoning that sexual reproduction by C. reinhardtii requires extensive communication between cells, we used mass spectrometry to identify proteins recovered from the soluble secretome of mating gametes, and searched for evidence that the putative peptidergic processing enzymes were functional. After fractionation by SDS-PAGE, signal peptide-containing proteins that remained intact, and those that had been subjected to cleavage, were identified. The C. reinhardtii mating secretome contained multiple matrix metalloproteinases, cysteine endopeptidases, and serine carboxypeptidases, along with one subtilisin-like proteinase. Published transcriptomic studies support a role for these proteases in sexual reproduction. Multiple extracellular matrix proteins (ECM) were identified in the secretome. Several pherophorins, ECM glycoproteins homologous to the Volvox sex-inducing pheromone, were present; most contained typical peptide processing sites, and many had been cleaved, generating stable N- or C-terminal fragments. Our data suggest that subtilisin endoproteases and matrix metalloproteinases similar to those important in vertebrate peptidergic and growth factor signaling play an important role in stage transitions during the life cycle of C. reinhardtii. Full article
(This article belongs to the Special Issue Neuroproteomics)
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22 pages, 3254 KiB  
Article
Granulocyte-Colony-Stimulating Factor Alters the Proteomic Landscape of the Ventral Tegmental Area
by Nicholas L. Mervosh, Rashaun Wilson, Navin Rauniyar, Rebecca S. Hofford, Munir Gunes Kutlu, Erin S. Calipari, TuKiet T. Lam and Drew D. Kiraly
Proteomes 2018, 6(4), 35; https://doi.org/10.3390/proteomes6040035 - 23 Sep 2018
Cited by 9 | Viewed by 5673
Abstract
Cocaine addiction is characterized by aberrant plasticity of the mesolimbic dopamine circuit, leading to dysregulation of motivation to seek and take drug. Despite the significant toll that cocaine use disorder exacts on society, there are currently no available pharmacotherapies. We have recently identified [...] Read more.
Cocaine addiction is characterized by aberrant plasticity of the mesolimbic dopamine circuit, leading to dysregulation of motivation to seek and take drug. Despite the significant toll that cocaine use disorder exacts on society, there are currently no available pharmacotherapies. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a soluble cytokine that alters the behavioral response to cocaine and which increases dopamine release from the ventral tegmental area (VTA). Despite these known effects on behavior and neurophysiology, the molecular mechanisms by which G-CSF affects brain function are unclear. In this study mice were treated with repeated injections of G-CSF, cocaine or a combination and changes in protein expression in the VTA were examined using an unbiased proteomics approach. Repeated G-CSF treatment resulted in alterations in multiple signaling pathways related to synaptic plasticity and neuronal morphology. While the treatment groups had marked overlap in their effect, injections of cocaine and the combination of cocaine and G-CSF lead to distinct patterns of significantly regulated proteins. These experiments provide valuable information as to the molecular pathways that G-CSF activates in an important limbic brain region and will help to guide further characterization of G-CSF function and evaluation as a possible translational target. Full article
(This article belongs to the Special Issue Neuroproteomics)
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18 pages, 3210 KiB  
Article
Regional Diversity in the Postsynaptic Proteome of the Mouse Brain
by Marcia Roy, Oksana Sorokina, Colin McLean, Silvia Tapia-González, Javier DeFelipe, J. Douglas Armstrong and Seth G. N. Grant
Proteomes 2018, 6(3), 31; https://doi.org/10.3390/proteomes6030031 - 1 Aug 2018
Cited by 30 | Viewed by 8678
Abstract
The proteome of the postsynaptic terminal of excitatory synapses comprises over one thousand proteins in vertebrate species and plays a central role in behavior and brain disease. The brain is organized into anatomically distinct regions and whether the synapse proteome differs across these [...] Read more.
The proteome of the postsynaptic terminal of excitatory synapses comprises over one thousand proteins in vertebrate species and plays a central role in behavior and brain disease. The brain is organized into anatomically distinct regions and whether the synapse proteome differs across these regions is poorly understood. Postsynaptic proteomes were isolated from seven forebrain and hindbrain regions in mice and their composition determined using proteomic mass spectrometry. Seventy-four percent of proteins showed differential expression and each region displayed a unique compositional signature. These signatures correlated with the anatomical divisions of the brain and their embryological origins. Biochemical pathways controlling plasticity and disease, protein interaction networks and individual proteins involved with cognition all showed differential regional expression. Combining proteomic and connectomic data shows that interconnected regions have specific proteome signatures. Diversity in synapse proteome composition is key feature of mouse and human brain structure. Full article
(This article belongs to the Special Issue Neuroproteomics)
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Review

Jump to: Editorial, Research, Other

23 pages, 1091 KiB  
Review
Cell-Type-Specific Proteomics: A Neuroscience Perspective
by Rashaun S. Wilson and Angus C. Nairn
Proteomes 2018, 6(4), 51; https://doi.org/10.3390/proteomes6040051 - 9 Dec 2018
Cited by 28 | Viewed by 6381
Abstract
Cell-type-specific analysis has become a major focus for many investigators in the field of neuroscience, particularly because of the large number of different cell populations found in brain tissue that play roles in a variety of developmental and behavioral disorders. However, isolation of [...] Read more.
Cell-type-specific analysis has become a major focus for many investigators in the field of neuroscience, particularly because of the large number of different cell populations found in brain tissue that play roles in a variety of developmental and behavioral disorders. However, isolation of these specific cell types can be challenging due to their nonuniformity and complex projections to different brain regions. Moreover, many analytical techniques used for protein detection and quantitation remain insensitive to the low amounts of protein extracted from specific cell populations. Despite these challenges, methods to improve proteomic yield and increase resolution continue to develop at a rapid rate. In this review, we highlight the importance of cell-type-specific proteomics in neuroscience and the technical difficulties associated. Furthermore, current progress and technological advancements in cell-type-specific proteomics research are discussed with an emphasis in neuroscience. Full article
(This article belongs to the Special Issue Neuroproteomics)
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18 pages, 2267 KiB  
Review
From Synapse to Function: A Perspective on the Role of Neuroproteomics in Elucidating Mechanisms of Drug Addiction
by Luis A. Natividad, Matthew W. Buczynski, Daniel B. McClatchy and John R. Yates III
Proteomes 2018, 6(4), 50; https://doi.org/10.3390/proteomes6040050 - 9 Dec 2018
Cited by 14 | Viewed by 5579
Abstract
Drug addiction is a complex disorder driven by dysregulation in molecular signaling across several different brain regions. Limited therapeutic options currently exist for treating drug addiction and related psychiatric disorders in clinical populations, largely due to our incomplete understanding of the molecular pathways [...] Read more.
Drug addiction is a complex disorder driven by dysregulation in molecular signaling across several different brain regions. Limited therapeutic options currently exist for treating drug addiction and related psychiatric disorders in clinical populations, largely due to our incomplete understanding of the molecular pathways that influence addiction pathology. Recent work provides strong evidence that addiction-related behaviors emerge from the convergence of many subtle changes in molecular signaling networks that include neuropeptides (neuropeptidome), protein-protein interactions (interactome) and post-translational modifications such as protein phosphorylation (phosphoproteome). Advancements in mass spectrometry methodology are well positioned to identify these novel molecular underpinnings of addiction and further translate these findings into druggable targets for therapeutic development. In this review, we provide a general perspective of the utility of novel mass spectrometry-based approaches for addressing critical questions in addiction neuroscience, highlighting recent innovative studies that exemplify how functional assessments of the neuroproteome can provide insight into the mechanisms of drug addiction. Full article
(This article belongs to the Special Issue Neuroproteomics)
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12 pages, 631 KiB  
Review
Deep Profiling of the Aggregated Proteome in Alzheimer’s Disease: From Pathology to Disease Mechanisms
by Brianna M. Lutz and Junmin Peng
Proteomes 2018, 6(4), 46; https://doi.org/10.3390/proteomes6040046 - 12 Nov 2018
Cited by 23 | Viewed by 6571
Abstract
Hallmarks of Alzheimer’s disease (AD), a progressive neurodegenerative disease causing dementia, include protein aggregates such as amyloid beta plaques and tau neurofibrillary tangles in a patient’s brain. Understanding the complete composition and structure of protein aggregates in AD can shed light on the [...] Read more.
Hallmarks of Alzheimer’s disease (AD), a progressive neurodegenerative disease causing dementia, include protein aggregates such as amyloid beta plaques and tau neurofibrillary tangles in a patient’s brain. Understanding the complete composition and structure of protein aggregates in AD can shed light on the as-yet unidentified underlying mechanisms of AD development and progression. Biochemical isolation of aggregates coupled with mass spectrometry (MS) provides a comprehensive proteomic analysis of aggregates in AD. Dissection of these AD-specific aggregate components, such as U1 small nuclear ribonucleoprotein complex (U1 snRNP), provides novel insights into the deregulation of RNA splicing in the disease. In this review, we summarize the methodologies of laser capture microdissection (LCM) and differential extraction to analyze the aggregated proteomes in AD samples, and discuss the derived novel insights that may contribute to AD pathogenesis. Full article
(This article belongs to the Special Issue Neuroproteomics)
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13 pages, 1056 KiB  
Review
Phosphorylation of the AMPAR-TARP Complex in Synaptic Plasticity
by Joongkyu Park
Proteomes 2018, 6(4), 40; https://doi.org/10.3390/proteomes6040040 - 8 Oct 2018
Cited by 10 | Viewed by 7083
Abstract
Synaptic plasticity has been considered a key mechanism underlying many brain functions including learning, memory, and drug addiction. An increase or decrease in synaptic activity of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complex mediates the phenomena as shown in the cellular models of synaptic [...] Read more.
Synaptic plasticity has been considered a key mechanism underlying many brain functions including learning, memory, and drug addiction. An increase or decrease in synaptic activity of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complex mediates the phenomena as shown in the cellular models of synaptic plasticity, long-term potentiation (LTP), and depression (LTD). In particular, protein phosphorylation shares the spotlight in expressing the synaptic plasticity. This review summarizes the studies on phosphorylation of the AMPAR pore-forming subunits and auxiliary proteins including transmembrane AMPA receptor regulatory proteins (TARPs) and discusses its role in synaptic plasticity. Full article
(This article belongs to the Special Issue Neuroproteomics)
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15 pages, 1904 KiB  
Review
Exploring Morphine-Triggered PKC-Targets and Their Interaction with Signaling Pathways Leading to Pain via TrkA
by Darlene A. Pena, Mariana Lemos Duarte, Dimitrius T. Pramio, Lakshmi A. Devi and Deborah Schechtman
Proteomes 2018, 6(4), 39; https://doi.org/10.3390/proteomes6040039 - 6 Oct 2018
Cited by 15 | Viewed by 9900
Abstract
It is well accepted that treatment of chronic pain with morphine leads to μ opioid receptor (MOR) desensitization and the development of morphine tolerance. MOR activation by the selective peptide agonist, D-Ala2, N-MePhe4, Gly-ol]-enkephalin(DAMGO), leads to robust G protein receptor kinase activation, β-arrestin [...] Read more.
It is well accepted that treatment of chronic pain with morphine leads to μ opioid receptor (MOR) desensitization and the development of morphine tolerance. MOR activation by the selective peptide agonist, D-Ala2, N-MePhe4, Gly-ol]-enkephalin(DAMGO), leads to robust G protein receptor kinase activation, β-arrestin recruitment, and subsequent receptor endocytosis, which does not occur in an activation by morphine. However, MOR activation by morphine induces receptor desensitization, in a Protein kinase C (PKC) dependent manner. PKC inhibitors have been reported to decrease receptor desensitization, reduce opiate tolerance, and increase analgesia. However, the exact role of PKC in these processes is not clearly delineated. The difficulties in establishing a particular role for PKC have been, in part, due to the lack of reagents that allow the selective identification of PKC targets. Recently, we generated a conformation state-specific anti-PKC antibody that preferentially recognizes the active state of this kinase. Using this antibody to selectively isolate PKC substrates and a proteomics strategy to establish the identity of the proteins, we examined the effect of morphine treatment on the PKC targets. We found an enhanced interaction of a number of proteins with active PKC, in the presence of morphine. In this article, we discuss the role of these proteins in PKC-mediated MOR desensitization and analgesia. In addition, we posit a role for some of these proteins in mediating pain by TrKA activation, via the activation of transient receptor potential cation channel subfamily V member 1 (TRPV1). Finally, we discuss how these new PKC interacting proteins and pathways could be targeted for the treatment of pain. Full article
(This article belongs to the Special Issue Neuroproteomics)
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21 pages, 726 KiB  
Review
Proteomic Approaches for the Discovery of Biofluid Biomarkers of Neurodegenerative Dementias
by Becky C. Carlyle, Bianca A. Trombetta and Steven E. Arnold
Proteomes 2018, 6(3), 32; https://doi.org/10.3390/proteomes6030032 - 31 Aug 2018
Cited by 48 | Viewed by 8276
Abstract
Neurodegenerative dementias are highly complex disorders driven by vicious cycles of intersecting pathophysiologies. While most can be definitively diagnosed by the presence of disease-specific pathology in the brain at postmortem examination, clinical disease presentations often involve substantially overlapping cognitive, behavioral, and functional impairment [...] Read more.
Neurodegenerative dementias are highly complex disorders driven by vicious cycles of intersecting pathophysiologies. While most can be definitively diagnosed by the presence of disease-specific pathology in the brain at postmortem examination, clinical disease presentations often involve substantially overlapping cognitive, behavioral, and functional impairment profiles that hamper accurate diagnosis of the specific disease. As global demographics shift towards an aging population in developed countries, clinicians need more sensitive and specific diagnostic tools to appropriately diagnose, monitor, and treat neurodegenerative conditions. This review is intended as an overview of how modern proteomic techniques (liquid chromatography mass spectrometry (LC-MS/MS) and advanced capture-based technologies) may contribute to the discovery and establishment of better biofluid biomarkers for neurodegenerative disease, and the limitations of these techniques. The review highlights some of the more interesting technical innovations and common themes in the field but is not intended to be an exhaustive systematic review of studies to date. Finally, we discuss clear reporting principles that should be integrated into all studies going forward to ensure data is presented in sufficient detail to allow meaningful comparisons across studies. Full article
(This article belongs to the Special Issue Neuroproteomics)
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12 pages, 2441 KiB  
Review
Uncovering Discrete Synaptic Proteomes to Understand Neurological Disorders
by Yi-Zhi Wang and Jeffrey N. Savas
Proteomes 2018, 6(3), 30; https://doi.org/10.3390/proteomes6030030 - 19 Jul 2018
Cited by 9 | Viewed by 5701
Abstract
The mammalian nervous system is an immensely heterogeneous organ composed of a diverse collection of neuronal types that interconnect in complex patterns. Synapses are highly specialized neuronal cell-cell junctions with common and distinct functional characteristics that are governed by their protein composition or [...] Read more.
The mammalian nervous system is an immensely heterogeneous organ composed of a diverse collection of neuronal types that interconnect in complex patterns. Synapses are highly specialized neuronal cell-cell junctions with common and distinct functional characteristics that are governed by their protein composition or synaptic proteomes. Even a single neuron can possess a wide-range of different synapse types and each synapse contains hundreds or even thousands of proteins. Many neurological disorders and diseases are caused by synaptic dysfunction within discrete neuronal populations. Mass spectrometry (MS)-based proteomic analysis has emerged as a powerful strategy to characterize synaptic proteomes and potentially identify disease driving synaptic alterations. However, most traditional synaptic proteomic analyses have been limited by molecular averaging of proteins from multiple types of neurons and synapses. Recently, several new strategies have emerged to tackle the ‘averaging problem’. In this review, we summarize recent advancements in our ability to characterize neuron-type specific and synapse-type specific proteomes and discuss strengths and limitations of these emerging analysis strategies. Full article
(This article belongs to the Special Issue Neuroproteomics)
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1 pages, 139 KiB  
Correction
Correction: Baucum II, Anthony J. et al. Proteomic Analysis of the Spinophilin Interactome in Rodent Striatum Following Psychostimulant Sensitization. Proteomes 2018, 6, 53
by Darryl S. Watkins, Jason D. True, Amber L. Mosley and Anthony J. Baucum
Proteomes 2019, 7(1), 7; https://doi.org/10.3390/proteomes7010007 - 13 Feb 2019
Cited by 1 | Viewed by 2470
Abstract
The author wishes to make the following corrections to the methods section of their paper [...] Full article
(This article belongs to the Special Issue Neuroproteomics)
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