Dataset Information

The Transglutaminase-2 interactome in the APP23 mouse model of Alzheimer disease

ABSTRACT: Amyloid-beta (Aβ) deposition in the brain, is closely linked to development of Alzheimer’s disease (AD). Unfortunately, therapies specifically targeting Aβ deposition have failed to reach their primary clinical endpoints, emphasizing the need to broaden the search strategy for identification of alternative therapeutic targets/mechanisms. Transglutaminase (TG2) catalyses posttranslational modifications, is present in characteristic AD lesions and has AD-associated proteins, including Aβ, tau and apolipoprotein E. However, an unbiased overview of TG2 interactors (TG2 interactome) and the cellular pathways of which these interactors are part in control and AD brain is lacking. Here, anticipating future studies in AD brain, we aimed to identify these interactors and their pathways using a crossbred of the AD-mimicking APP23 mouse model with wildtype and TG2-/- mice. We found that absence of TG2 had no (statistically) significant effect on Aβ pathology, soluble brain levels of Aβ1-40, Aβ1-42, and mRNA levels of TG2 family members compared to APP23 mice. Quantitative proteomics and network analysis revealed a large cluster of TG2 interactors with synaptic transmission/assembly and cell adhesion typical of AD in the APP23 brain. Comparative proteomics were in line with these observations as it also revealed association of proteins of both pathways to be linked to TG2 in APP23 brains Together, our data showed that TG2 deletion led to considerable network alterations consistent with a role of TG2 in (dys)regulation of synaptic transmission and cell adhesion in APP23 brains.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: David Boocock

LAB HEAD: David Boocock

PROVIDER: PXD030354 | Pride | 2022-02-22

REPOSITORIES: Pride

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Publications

The Transglutaminase-2 Interactome in the APP23 Mouse Model of Alzheimer's Disease.

Wilhelmus Micha M M MMM Tonoli Elisa E Coveney Clare C Boocock David J DJ Jongenelen Cornelis A M CAM Brevé John J P JJP Verderio Elisabetta A M EAM Drukarch Benjamin B

Cells 20220124 3

Amyloid-beta (Aβ) deposition in the brain is closely linked with the development of Alzheimer's disease (AD). Unfortunately, therapies specifically targeting Aβ deposition have failed to reach their primary clinical endpoints, emphasizing the need to broaden the search strategy for alternative targets/mechanisms. Transglutaminase-2 (TG2) catalyzes post-translational modifications, is present in AD lesions and interacts with AD-associated proteins. However, an unbiased overview of TG2 interactors ...[more]

PMID: 35159198

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Project description:Celiac disease (CD) is a chronic inflammation of the small intestine triggered by the ingestion of gluten in genetically predisposed individuals. Tissue transglutaminase (TG2) is a key factor in the pathogenesis of CD, because it catalyzes both the deamidation of specific glutamine residues and the formation of covalent Nε-(γ-glutamyl)-lysine isopeptide crosslinks resulting in TG2-gluten peptide complexes. These complexes are thought to activate B cells causing the secretion of anti-TG2 autoantibodies that serve as diagnostic markers for CD, although their pathogenic role remains unclear. To gain more insight into the molecular structures of TG2-gluten peptide complexes, we developed a reciprocal proteomic analysis strategy, which facilitates the comprehensive identification of isopeptides in a complex protein hydrolysate. The workflow consists of four steps: (1) performance of the model reaction between TG2 and gluten peptide(s) followed by tryptic hydrolysis, clean-up and untargeted nLC-MS/MS analysis (2), prediction of tryptic TG2-derived lysine peptides that serve as potential isopeptide modifications (3) the search for isopeptides by configuring the TG2-modifications in MaxQuant and search against the α-gliadin fasta file and (4) the reciprocal search for isopeptides by configuring the gluten peptide(s) as modification in MaxQuant and search against the TG2 fasta file. After verification by manual data curation and visualization, this strategy enabled the identification of 26 different isopeptides involving 19 TG2 lysine residues, only six of which were known previously. Experiments with different TG2-gluten peptide molar ratios revealed that K-425, K-590, K-600 and K-649 were the most preferred lysine residues involved in isopeptide crosslinking. Further, expanding the model system to three gluten peptides allowed the localization of the preferred glutamine crosslinking sites. The described strategy is generally applicable to any hydrolysate containing isopeptides and these new insights into the structure of TG2-gluten peptide complexes may help clarify the role of extracellular TG2 in CD autoimmunity and in other inflammatory diseases.

Project description:Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1 This model is described in the article: Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. J. Clin. Invest. 2011 Oct; 121(10): 3924-3931 Abstract: In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD. This model is hosted on BioModels Database and identified by: BIOMD0000000618. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

The Transglutaminase-2 interactome in the APP23 mouse model of Alzheimer disease

Publications

The Transglutaminase-2 Interactome in the APP23 Mouse Model of Alzheimer's Disease.

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