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In-depth protein profiling of mouse hippocampal postsynaptic density using data-independent acquisition proteomics

ABSTRACT: In the present study, we catalogued the proteome of postsynaptic density (PSD) derived from the hippocampus of three-week old (P19) mice. samples in 100 min gradient time.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hippocampus

SUBMITTER: Ute Distler

LAB HEAD: Ute Distler

PROVIDER: PXD000590 | Pride | 2014-09-25

REPOSITORIES: Pride

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			Action	DRS
	Distler_et_al_peptide_report_fractions.xlsx	Xlsx
	Distler_et_al_protein_report_fractions.xlsx	Xlsx
	P2-A1.raw.zip	Raw
	P2-A2.raw.zip	Raw
	P2-A3.raw.zip	Raw

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Publications

In-depth protein profiling of the postsynaptic density from mouse hippocampus using data-independent acquisition proteomics.

Distler Ute U Schmeisser Michael J MJ Pelosi Assunta A Reim Dominik D Kuharev Jörg J Weiczner Roland R Baumgart Jan J Boeckers Tobias M TM Nitsch Robert R Vogt Johannes J Tenzer Stefan S

Proteomics 20141018 21-22

Located at neuronal terminals, the postsynaptic density (PSD) is a highly complex network of cytoskeletal scaffolding and signaling proteins responsible for the transduction and modulation of glutamatergic signaling between neurons. Using ion-mobility enhanced data-independent label-free LC-MS/MS, we established a reference proteome of crude synaptosomes, synaptic junctions, and PSD derived from mouse hippocampus including TOP3-based absolute quantification values for identified proteins. The fi ...[more]

PMID: 25211037

Similar Datasets

In-depth protein profiling of mouse hippocampal postsynaptic density using data-independent acquisition proteomics

Project description:In the present study, we catalogued the proteome of postsynaptic density (PSD) derived from the hippocampus of three-week old (P19) mice. samples in 100 min gradient time.

2019-08-27 | MSV000084240 | MassIVE

Developmental profile of core postsynaptic density protein complexes integrates signaling components of brain disorders

Project description:The postsynaptic density (PSD) contains a collection of scaffold proteins used for the assembly of synaptic signaling complexes and disruption of this signaling machinery might be implicated in a variety of brain disorders. However, it is not known how the core-scaffold machinery associates this collection of proteins through development and how proteins coding for genes involved in psychiatric and other brain disorders are distributed through spatio-temporal protein complexes. Here, using immunopurification, proteomics, bioinformatics and mouse genetics, we isolated 2876 proteins across 41 in-vivo protein complexes and determined their protein domain composition, correlation to gene expression levels, and developmental integration to the PSD. We defined major protein clusters for enrichment of schizophrenia (SCZ), autism spectrum disorders (ASD), developmental delay (DD), and intellectual disability (ID) risk factors at embryonic day 14 and the adult PSD. These protein complexes contained a discrete number of protein domains defining molecular functions. Mutations in highly-connected nodes alter protein-protein interactions that modulate the assembly of macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform: Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of brain disease risk factors and their placement within synaptic protein interaction networks.

2017-08-22 | PXD006277 | Pride

Unbiased proteomic analysis of postsynaptic density fractions from Shank3 mutant mice reveals brain region specific changes highly relevant to autism spectrum disorder

Project description:Disruption of the human SHANK3 gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome (PMS), autism spectrum disorders (ASDs) and intellectual disability (ID). Although a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the postsynaptic protein scaffold, the molecular processes at synapses of individuals harboring SHANK3 mutations are still far from being understood. In this study, we biochemically isolated the postsynaptic density (PSD) fraction from striatum and hippocampus of Shank3Δ11-/- mutant mice and performed ion-mobility enhanced data-independent label-free LC-MS/MS to obtain the corresponding PSD proteomes. This unbiased approach to identify molecular disturbances at PSDs devoid of major Shank3 isoforms revealed largely distinct molecular alterations in striatum and hippocampus. Being the first comprehensive analysis of brain region specific PSD proteomes from a Shank3 mutant line, our study provides crucial information on molecular alterations that could foster translational treatment studies for SHANK3 mutation-associated synaptopathies and possibly also ASD in general.

2017-03-08 | PXD005192 | Pride

Correlation profiling of synaptic sub-fraction proteomes of the mouse brain hippocampus, cortex and cerebellum

Project description:Synaptic transmission forms the main mode of signaling and information integration in the nervous system. Here, we identified and quantified proteins from three brain regions and five biochemical synapse sub-fractions. We identified around 4500 proteins in total, of which about 2000 proteins each were quantified from microsome, P2 fraction, synaptosome, synaptic membrane, and postsynaptic density (PSD). Correlation profiling using these data sets identified synaptic functional groups and showed enrichment of canonical presynaptic proteins in synaptosome, and canonical postsynaptic proteins in PSD. In addition, we detected profound brain region specific differences in the extent of enrichment for some functionally associated proteins, exemplified by different AMPAR subunits and the large differences in spatial distribution of their potential interactors. Furthermore, we revealed novel PSD proteins PLEKHA5 and ADGRA1, which using super-resolution microscopy on primary neuronal culture were confirmed to reside in the PSD.

2017-09-25 | PXD005634 | Pride

Mutations in the postsynaptic signaling hub TNIK disrupts neuronal progenitor cells and immature neuronal function in human models of neurodevelopmental disease

Project description:Synaptic proteins, in particular those connected in large protein interaction networks at the postsynaptic site of glutamatergic neurons have been associated to a number of neurodevelopmental disorders. While their contribution to disease has been well documented in mature rodent synapses, their role in early neuronal development and in non-neuronal cell types is not known. Additionally, it is unclear if they are associated in the same protein interaction networks (PINs) in early neuronal development, particularly in human models of neurodevelopmental disease. Here we use the postsynaptic density (PSD) protein TNIK as a model of a classical PSD signaling hub associated to neurodevelopmental disease. Using hiPSC models of TNIK disfunction and disease, we show that PSD PINs are dysregulated by TNIK in immature neurons, synapses and neuronal progenitor cells (NPCs). TNIK impairs NPCs and human immature synapses using different signaling mechanisms and associating to different sets of “PSD proteins”.

2024-03-26 | PXD035004 | Pride

Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment [2]

Project description:Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we utilize UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding for proteins known to interact with postsynaptic AMPA and NMDA receptors. Loci in/near Discs Large Homolog 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P<5x10-8) for BF% and/or BMI. To further evaluate the functional role of PSD-95 (gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PDZ-domain-targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising new therapeutic avenue for sustained weight loss.

2024-01-04 | GSE251836 | GEO

Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment

Project description:Abstract: Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we utilize UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding for proteins known to interact with postsynaptic AMPA and NMDA receptors. Loci in/near Discs Large MAGUK Scaffold Protein 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P<5x10-8) for BF% and/or BMI. To further evaluate the functional role of PSD-95 (gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PDZ-domain-targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising new therapeutic avenue for sustained weight loss.

2024-03-11 | GSE221549 | GEO

BAI1 localises AMPA receptors at the cochlear afferent postsynaptic density and is

Project description:Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming axo-somatic synapses with inner hair cells (IHCs), the primary sensory receptors of the mammalian cochlea. Although IHC ribbon synapses have been extensively studied, the molecular mechanisms regulating the structure and function of the post-synaptic density (PSD) at the SGN afferent terminals are largely unknown. Using functional, morphological, and transcriptomic approaches, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1), encoded by the Adgrb1 gene, is required for the clustering of the glutamate AMPA receptors GluR2-4 to the SGN post-synaptic density. Adult mice expressing BAI1 lacking the N-terminal thrombospondin type 1 repeats (TRS) have functional IHC synapses but fail to transmit acoustic information to the SGNs, leading to highly raised auditory thresholds. We also found that in adult Bai1-deficient mice, despite the almost complete absence of AMPA receptors, the SGN fibres innervating the IHCs did not degenerate. RNA sequencing and western blotting also indicate that AMPA receptors are expressed in the cochlea of Bai1-deficient mice, highlights that BAI1 is involved is trafficking or anchoring GluR2-4 to the PSDs. Moreover, these results have identified novel molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.

2024-03-27 | GSE254269 | GEO

Post-ischemic ubiquitination at the postsynaptic density reversibly influences the activity of ischemia-relevant kinases.

Project description:Posttranslational modifications with ubiquitin alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces protein ubiquitination at the periphery of the ischemic territory, wherein cells remain viable. Revealing the identity of ubiquitinated proteins, their cellular location, and the functional consequences of ubiquitin modification may shed light on the role of ubiquitination in ischemic injury. Here, we employed a proteomics approach to identify proteins ubiquitinated following ischemic stroke, induced by transient middle cerebral artery occlusion (tMCAO) in mice. We detected increased ubiquitination of 198 proteins, many of which localize to the postsynaptic density (PSD) of glutamatergic neurons. Among these were proteins essential for maintaining PSD architecture, such as PSD93, PSD95 and Shank3, as well as NMDA and AMPA receptor subunits. The largest enzymatic group at the PSD with high post-ischemic ubiquitination levels were kinases, such as CaMKII, PKC, Cdk5, and Pyk2, the aberrant activity of which contributes to post-ischemic neuronal death. Concurrent phospho-proteomics revealed altered phosphorylation patterns associated with the PSD, indicative of modified PSD kinase activity following stroke. CaMKII, PKC, and Cdk5 activity was decreased while Pyk2 activity was increased at the PSD after stroke, accompanied by the hypo- and hyper-phosphorylation of downstream targets, respectively. Removal of ubiquitin restored kinases’ activity to pre-stroke levels, identifying ubiquitination as the responsible molecular mechanism for post-ischemic kinase regulation. These findings unveil a previously unrecognized role of post-ischemic ubiquitination in the regulation of essential kinases involved in ischemic injury, and presents targeting ubiquitination as a potential new avenue for the treatment of ischemic stroke.

2023-09-06 | PXD042951 | Pride

Experience-induced remodeling of the hippocampal post-synaptic proteome and phosphoproteome

Project description:The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following 4 different types of experience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3,938 proteins and 2,761 phosphoproteins in the sequential strategy covering a total of 4,968 unique protein groups (at least 2 peptides including an unique peptide). On the phosphoproteins, we identified a total of 6,188 unambiguous phosphosites (75% site localization probability)

2024-01-26 | PXD045496 | Pride